User:Loganhardin/Leptospira interrogans

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The Lead Section could be more developed. The sources I checked out are reliable. Morphology could include more media. --Olivia


https://www.researchgate.net/profile/Nozha-Cohen/publication/234163768_LEPTOSPIRA_Morphology_Classification_and_Pathogenesis/links/0912f50fa9202220d4000000/LEPTOSPIRA-Morphology-Classification-and-Pathogenesis.pdf?_sg%5B0%5D=started_experiment_milestone&origin=journalDetail

The above article seems to have good information about morphology and pathogenesis. --Molly

https://www.frontiersin.org/articles/10.3389/fcimb.2021.708739/full[1]

The article above has a lot of detail about different diseases/how L. interrogans interacts with proteins to contribute to pathogenesis. --Logan

I've added an article that gives a lot of great info about Lepto metabolism, nutritional needs, and general features as well. I'll look into more articles in this area as well - Drew[2]

Here is an article about human-infecting Lepto in blood and serum samples collected. It details a novel sequence type and it's unique genome. -Olivia[3]

  • What I want to add to the "Genomics" section: Olivia
  • Human Pathogenicity: Olivia
    • How the disease is diagnosed: Currently, in best practices, the disease is diagnosed by a microscopic agglutination test, MAT, but this test is unable to detect the disease during early stages.[5] Combining diagnostic tests with a MAT, such as a PCR test, improves the diagnosis of the disease during its early stages.[6] Recent studies are improving the PCR tests in hopes to increase the diagnostic accuracy by utilizing tests that target 16S ribosomal RNA and lipl32 genes.[7]
      • More information on the lipl32 gene
        • LipL32 is a major protein in L. interrogans. Although, there is doubt regarding where this protein is located. Recent studies suggest that it is a subsurface membrane lipoprotein on the inner leaflet of the outer membrane.[8] Although the biological function of the protein is still unknown, it is suggested that lipL32 protein aids in the adherence to host cells.[9]
          • Additional information about the structural gene: rho-independent termination and protein is comprised of 272 amino acids.[10]
    • Utilizing 16s rRNA PCR testing is beneficial as treatment with antibiotics makes it difficult to detect infection through bacteria culture testing.[11] In a study conducted by Boonsilp et al., it was found that a proportion of patients who were found to be negative utilizing bacteria culture testing were found to be positive through 16S rRNA PCR testing, which they contribute to the “ready availability of over the counter antibiotics.” [11] So, utilizing 16S rRNA gene sequencing is advantageous as it is culture independent. Additionally, culturing L. interrogans is very difficult as they are slow growing, with an average generation time between 15-23 hours, so observing positive cultural growth may take several weeks following collection of a culture, typically up to three months.[12]
      • Add information about why using 16S rRNA is beneficial ^ I think the info I added explains why this is beneficial, feel free to add any additional info you find
  • Sentence structure change: Olivia The spirochete pathogen Leptospira interrogans is the main cause of human leptospirosis. In humans, disease caused by L. interrogans is classified as either icteric or anicteric. The spirochete pathogen Leptospira interrogans is the main cause of human leptospirosis. In humans, symptoms caused by L. interrogans are biphasic, icteric or anicteric.


Feedback from Peer Review --Molly

  • Add more info about metabolism; add to morphology & genomics sections
  • Add a vaccine section--> more info about disease in domestic dogs, especially since this is mentioned in lead section (vaccine for dogs that is not mentioned at in article)
  • Add more info to lead section
  • More images

Feedback from peer review-- Olivia

I agree with the feedback about mentioning the disease in domestic dogs. I also want to mention how the disease is spread especially after hurricanes by contaminated water.

  • Additional Metabolism - Drew
    • (Adding to the point about E and C source) - Through naturally occurring phase interfaces or its growth media, L. interrogans must physically obtain the long chain fatty acids in order to further metabolize them as an energy source. [2]
    • (Interesting point here - I just took the direct quote for now so I don't forget the info and I'll re-word it later) - "In contrast, growth of L. interrogans requires the presence of long chain unsaturated fatty acids; only in the presence of unsaturated fatty acids is L. interrogans able to metabolize saturated fatty acids." [2]
    • ATP production through oxidative phosphorylation. [2]
    • Evidence has been also shown that peroxides (ex. H2O2) can also serve as a terminal electron acceptor. [2]
    • L. Interrogans contains genes that code for the use of the TCA cycle in its metabolism. [2]
    • Catalase activity necessary to survive in vivo. [2]
    • It is a type of obligate aerobe bacteria.
  • More assorted information from a second source - Drew
    • some Morphology info from source - demonstrated diminished circular mobility in liquid and semi-solid media with the flagellar motor switch [13]
    • In vitro cultivation - Ability to persist for extended amounts of time in areas like moist soil and freshwater, which are considered areas with lower amounts of nutrients to give it time to encounter a mammalian host. [13]
      • Varying levels of survivability based on salinity, viscosity, and pH, among other factors. [13]
    • Some additional Animal pathogenicity info from source - A study with zebrafish embryos quantifying further study on L. interrogans pathogenesis showed that ones that were infected were asymptomatic during the onset of infection. It was shown that though the bacteria were able to survive in the macrophages when engulfed, and that the bacteria was able to spread via the infected macrophages. [13]
    • info Source https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037011/ [13]
    • Biofilms - Observed in a rat study system, L. interrogans biofilm formation was shown upon colonization in the renal area of these animals[14]
  • Growth and Virulence Factors - Drew
    • It has been shown in studies that L. interrogans may damage the endothelial cell lining of various vessels and organs, allowing them to leak and further spread the bacterium to other parts of the body. [15]
    • To allow itself to have the necessary energy to grow in hosts, methods like oxidative stress are used by the bacterium to take over host functions for its own benefit.[16]
    • The bacterial chaperone ClpB is a major driver in the overall virulence of L. interrogans aiding in overall survival inside a host, controlling stress response, as well as a unique role of protein disaggregation, contributing to increased virulence and pathogenicity. [16]
    • A characteristic of L. interrogans that it possesses no observable secretion abilities despite residing extracellular.[17]
    • Due to translocation characteristics, it has been shown that it does not stay within animal cells during infection cycle.[17]

^ I mention virulence factors above- Loa22, but please continue to add info if you find - Olivia

- A general point for the lead - L. interrogans emcompasses the pathogenic species of all leptospires. [13]

  • Additional Content for who is at risk --Olivia

Persons at risk of becoming infected with leptospirosis are those living under conditions where water and soil conditions may be contaminated with urine of infected animals. [18] Occupations at higher risks of becoming infected include those such as farmers, veterinarians, and military personal who regularly work outdoors in fields or with animals. [19]

Risk of becoming infected is increased following hurricanes and heavy storms, as soil containing animal urine can runoff and contaminate floodwater. As a way to prevent infection by L. interrogans, the CDC recommends covering wounds with waterproof bandages to seal out possibly contaminated water and to wear waterproof protective clothing.[19]

•Pathogenicity in humans

-More information from article on human leptospirosis: "Leptospirosis cause is due to a pathogenic gram-negative bacteria in which are found in 90 species and over 300 serovars" (Vincent et al., 2019). A species of rodents (Rattus norvegicus) are asymptomatic carriers of the virus.

-Humans can contract the virus often through cuts on the skin when they are exposed to any source of the virus (mainly through contaminated soil/water).

-The effect of the virus can be in the range of mild symptoms including fever and headache to more severe and chronic conditions such as jaundice and hemorrhages (Trevejo et al., 1998). More information on the different severe conditions are in the links below[3].

-We could maybe include a section of a case study that found epidemic leptospirosis to be a major contributor to hemorrhages in Nicaragua in 1995 (article below with some background)

https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0007270

https://academic.oup.com/jid/article/178/5/1457/810680?login=false

-Logan

Dog pathogenicity: Molly

https://www.sciencedirect.com/science/article/abs/pii/S0882401014001089?via%3Dihub

  • Leptospirosis in canines can be divided into the four categories of reproductive, icteric, hemorrhagic, and uremic. Reproductive leptospirosis results in the premature birth of offspring or abortion, and uremic leptospirosis is referred to as Stuttgart disease. L. interrogans triggers a highly inflammatory response in infected dogs. This inflammatory response results in the high expression of tumor necrosis factor alpha, referred to as TNF-α, in the uterine tissue of infected dogs. Interleukin-1β and interleukein-6. also exhibited increased levels of expression upon infection. Furthermore, L. interrogans is proven to result in the down-regulation of extracellular matrix (ECM) mRNA and proteins. These factors are likely correlated with the high susceptibility of canines to leptospirosis.[20]

https://avmajournals.avma.org/view/journals/ajvr/66/10/ajvr.2005.66.1780.xml

Adding media: Olivia

  • I have reached out to Drs. Natarajaseenivasan of "Pathogenic, diagnostic and vaccine potential of leptospiral outer membrane proteins (OMPs)"[21] and Dr. Haake of "The Leptospiral Outer Membrane"[22] for permission to use their figures in our Wiki page. I am waiting for a response from them.
    • Out of the many sources I reached out to, only 3-4 responded and granted permission upon paying $75-150.

Some outer membrane proteins, such as OmpL1, aid in the infection process of L. interrogans by allowing adherence to host cells's surface molecules. [23]

As L. interrogans is an obligate aerobe, reactive oxygen species (ROS) must be avoided during metabolism. PerRA and PerRB are genes encoding peroxide responsive regulators, and these regulators promote host adaptation as they contain approximately 17 genes which aid in signaling. [24]


New reference: Molly

https://www.nature.com/articles/nature01597

Current genomics section:

The L. interrogans genome consists of two circular chromosomes. The larger chromosome has a total genome size of 4.3 Mbp, and the smaller chromosome has a size of 350-360Kbp. It has a G+C content of 35-36% and contains 3,700-4,700 protein-coding genes, depending on the strain.

  • Leptospira is one of the few genera of the spirochaete phylum causing severe mammalian infect (cite).

Updated genomics section:

The L. interrogans genome consists of two circular chromosomes composed of a total of almost 4.7 Mbp (cite both articles). The larger chromosome (CI) has a total genome size of roughly 4.3 Mbp, and the smaller chromosome (CII) has a size of 350-360 Kbp. It has a G+C content of 35-36% and contains 3,700-4,700 protein-coding genes, depending on the strain. Approximately 4,360 genes are on CI, and 367 are on CII. Only 37 of these genes encode for transfer RNAs, and the bacteria also has a low number of rRNA encoding genes. All rRNA and tRNA genes are located on CI, along with most genes related to growth.

Genes specifically encoding for long-chain fatty-acid utilization, the TCA cycle, and electron transport chain have also been identified in L. interrogans. The detection of such genes confirms the use of oxidative phosphorylation as the primary metabolic pathway of L. interrogans. A large amount of genes related to eukaryotic cell invasion, cell attachment, and motility have been discovered. L. interrogans also has a complex set of genes associated with chemotaxis, more so than other pathogenic bacteria such as B. burgdorferi and T. palladium. Such genes able L. interrogans to be such a successful pathogen (cite!).

Pathogenesis section addition:

Weil's syndrome is an illness caused by a severe reaction from leptospirosis [13] Renal and hepatic failure can occur as well, which can lead to death[13]

Genomics section addition:

Leptospires are helically coiled and include a hooked end that appears to resemble a question mark shape.[13] Leptospires also exhibit mobility properties with the use of flagella and endoflagella located at the end portion of the bacteria. [13]

--Logan

Stress responses seen in L. interrogans include up-regulation expression of genes encoding proteins such as chaperone proteins including clpA, heat shock proteins including GroEL, and endoflagellar proteins including flgA.[25]

-Olivia


Adding this image under "Genomics" -represents the two circular chromosomes of L. interrogans serovar Lai

-Olivia

L. interrogans has a rather complex chemotaxis system compared to other pathogenic microbes, likely contributing to its effectiveness as a pathogen. Virulence is also related to the leptospiral LPS, which is known to uniquely activate macrophages.

-Molly


Prophages may provide bacteria with beneficial genes, such as antibiotic resistance genes, influencing the bacteria's fitness.

Adding information about phage:

Following genome sequencing, it was discovered that prophages, such as TA-TA and TG-CA, have been identified in L. interrogans.[26] Prophages play a vital role in virulence as they can provide the bacteria with beneficial genes, such as antibiotic resistance genes.[27][28]

More info to come soon ^

- Olivia

Antibiotics: can probably be added to existing area of article

Prior to the development of LVW, Leptospira Vanaporn Wuthiekanun agar, there was no accepted standard method of testing activity of antibiotic agents against L. interrogans. This is because the LVW agar is solid, not a liquid or semisolid medium as was used to culture L. interrogans in the past.[29] This solid agar allows for disk diffusion testing of L. interrogans against several antimicrobials.[30] In a study conducted by Wuthiekanun et al. seven L. interrogans serovars were grown on LVW agar plates and disk diffusion tests was conducted to test the susceptibility of the bacteria against several antimicrobials. [31] Susceptibility is calculated by using a ruler to measure the sizes of zones of inhibition, diameters around the disks infused with antimicrobials in which bacteria are unable to grow due to its presence. These measured diameters are then compared to a guidelines chart published by the Clinical and Laboratory Standards Institute. For each antimicrobial, it is determined whether the zone size is susceptible, intermediate, or resistant. [32] They found that all L. interrogans serovars were susceptible to the following antimicrobials: amomxicillin/clavulanic acid, amoxicillin, azithromycin, cefoxitin, ceftazidime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin, doripenem, doxycycline, gentamicin, linezolid, nitrofurantoin, penicillin, piperacillin/tazobactam, and tetracycline.[31] All serovars were found to be resistant to the following four antimicrobials, fosfomycin, nalidixic acid, rifampicin, and trimethoprim/sulfamethoxazole.[31]

Depiction of a disk diffusion test used to measure the effectiveness of varying antimicrobials. On the Petri dish on the left, the antibiotic disks are placed in agar media. After incubation, if the antimicrobial was effective in inhibiting bacterial growth, a zone of inhibition is seen, as depicted by disk "C".


Antimicrobials target specific aspects of a microbe's physiology. Such targets include the cell wall, DNA synthesis, RNA synthesis, protein synthesis, and metabolism.[33] Leptospirosis is commonly treated with the antibiotics penicillin and doxycycline. Penicillin belongs to a class of antibiotics known as Beta-lactam antibiotics, which target the cell wall.[33] Beta-lactam antibiotics inhibit bacterial growth by interfering with peptidoglycan synthesis.[34] The binding targets of Beta-lactams are known as penicillin binding proteins, PBPs. PBP enzymes including transpeptidase and transglycosylase are inhibited by the beta-lactam, preventing cross-linking of peptidoglycan peptides, leading to cell death.[35] Specifically in L. interrogans, the ponA and pbpB genes encode PBPs 1 and 3. Doxycycline belongs to a class of antibiotics known as Tetracyclines, which target protein synthesis. Tetracyclines block the binding of charged tRNAs to the A site of the ribosome.[33] Specifically, this antimicrobial affects the 30S subunit.

-Olivia


Classical diagnosis: this section was removed by CatPath- however, upon further review they did not see the articles specifically mention L. interrogans and its serovars.

Currently, in best practices, the disease is diagnosed by a microscopic agglutination test, MAT, but this test is unable to detect the disease during early stages.[5] Combining diagnostic tests with a MAT, such as a PCR test, improves the diagnosis of the disease during its early stages.[6] Recent studies are improving the PCR tests in hopes to increase the diagnostic accuracy by utilizing tests that target 16S ribosomal RNA and lipl32 genes.[7]

Utilizing 16s rRNA PCR testing is beneficial as treatment with antibiotics makes it difficult to detect infection through bacteria culture testing.[11] In a study conducted by Boonsilp et al., it was found that a proportion of patients who were found to be negative utilizing bacteria culture testing were found to be positive through 16S rRNA PCR testing, which they contribute to the “ready availability of over the counter antibiotics.” [11] Thus, utilizing 16S rRNA gene sequencing is advantageous as it is culture independent. Additionally, culturing L. interrogans is very difficult as they are slow growing, with an average generation time between 15-23 hours, so observing positive cultural growth may take several weeks following collection of a culture, typically up to three months.[12]

-Olivia


It is said by Said et al., specialists in infectious diseases, that '"Leptospira is the most common zoonotic disease worldwide."[36]

-Olivia


Virulence associated genes

Genomic flexibility, as described by Ramli et al., is seen by strains of L. interrogans possessing mobile elements.[37] Such mobile elements include plasmids, insertion sequences, and prophages.[37]

-Olivia

Stress responses: as well as the information regarding stress responses above- some more information about stress responses here:

Many L. interrogans serovars lack superoxide dismutase, SOD, which functions to convert the reactive oxygen ion superoxide into oxygen and hydrogen peroxide; therefore, other enzymes must replace this missing SOD. Among these enzymes that replace SOD are catalase, thiol peroxidase, and glutathione peroxidase.[38]

-Olivia

The flagella allow for translational and nontranslational movement.[38]


Adherence of the pathogen to host cells initiates the infection process.[38] Prior to adherence though, mobility plays a vital role as a virulence factor. Unlike other bacteria, L. interrogans possess two periplasmic flagella, which enable motility though connective tissues.[38]

adding more information about the importance of LipL32: One study suggests that LipL32 aids in virulence as well, as mutants led to quicker onset of clinical signs of Leptospirosis.[39]

More info about adhesion to host cell:

Alpha-like integrin proteins, Lig (leptospira immunoglobulin-like) proteins, and fibronectin-binding proteins (cadF), recognize ligands on the host cell surface, mediate host cell entry, and guide binding respectively.[38]

Once attachment has been successful, enzymes are released to degrade the host cell membranes. Among these enzymes include phospholipase A1 and lysophospholipase, which cleave triglyceride molecules into fragments and degrade matrix proteins for invasion respectively.[38] In addition to these enzymes, hemolysin proteins aid in pore-forming, and the creation of these transmembrane channels created in the host cells result in their damage.[38]


-Olivia


Look into biofilm formation, and any type of regulatory proteins- like repressors, find more info on phage,

F- factor? transformation?

Antibiotic resistance genes have been discovered within multiple serovars of L. interrogans. These genes contribute to mechanisms of antibiotic resistance by altering the target, degrading the antibiotic, modifying the antibiotic, and pumping the antibiotic out of the cell.[33][40] Within the Lai serovar, genes identified include vancomycin resistance proteins, acriflavine resistance proteins, and bacitracin resistance proteins.[38]

-Olivia

Transposable elements have also been found in L. interrogans. The Himar1 mariner transposon leads to efficient mutagenesis in L. interrogans.[41] This mutagenesis is deemed efficient as it occurs without specific requirements for recipient strains, such as the requirement of co-factors for insertion into a chromosome.[42]

-Olivia

Iron is a growth requirement for L. interrogans as it allows for various physiological processes to occur such as DNA replication, metabolism, and transcription.[43] For disease pathogenesis, haem acts as a major iron source.[44] Catabolism of haem is regulated by hmuO, a haem oxygenase. However, L. interrogans is capable of de novo synthesis of haem as well.[45] Biosynthesis of haem is regulated by the hemA operon. The hemA operon is comprised of the following genes hemA/C/D/B/L/E/N/G. HemR, a two-component system,TCS, acts simultaneously as a transcriptional repressor of hmuO and a transcriptional activator of hemA.[46]

-Olivia

Leptospira interrogans is a species of obligate aerobic spirochaete bacteria. Leptospira is one of the genera of the spirochaete phylum that causes severe mammalian infections. This species is pathogenic to some wild and domestic animals, including pet dogs. It can also spread to humans through abrasions on the skin, where infection can cause flu-like symptoms with kidney and liver damage. Human infections are commonly spread by contact with contaminated water or soil, often through the urine of both wild and domestic animals. Some populations of individuals are more susseptible to serious infection, including professions like farmers and veterinarians who work around animals. L. interrogans is mainly found in tropical regions, where waste treatment is underdeveloped. The bacterium exhibits two phases of infection including icteric or anicteric. The anicteric phase of infection is commonly known as phase 1 in which humans will exhibit fever, headache, and nausea, while the icteric phase or phase two includes more severe symptoms including hemorrhages and renal tubular failure. The main ways for testing for the presence of the bacterium and diagnosing diseased humans include the microscopic agglutination test (MAT) and PCR.The bacterium can live for weeks to months in ground or in water and can display many unique defense mechanisms to ensure its survival. L. interrogans contains many properties that ensure its optimal survival in specific conditions, including two periplasmic flagella for movement and mobility to more easily access and infect human and other mammialil tissue. In addition to its ability to infect hosts, the bacteria also exhibits the ability to use beta oxidation of long chain fatty acids for energy, in which includes oxygen and peroxides as its main terminal electron acceptors. L. interrogans contains two circular chromosomes, in which encode genes for evidence of its use of the TCA cycle and electron transport chain, revealing its use of oxidative phosphorylation for metabolism. The use of antimicrobials for treatment, including targeting certain aspects of the bacteria's physiology, can be affective in treatment of the disease. Leptospirosis is commonly treated in humans by the prescription of the antibiotics penicillin and doxycycline.

Updated lead section--Logan

Biofilms:

L. interrogans utilize the SAH pathway for quorum sensing. This quorum sensing leads to biofilm formation- which supports cell growth and aids in protection against environmental conditions that may be stressful.

Combining: Observed in a rat study system, L. interrogans biofilm formation was shown upon colonization in the renal area of these animals[14] : from Drew

Quorum sensing conducted by L. interrogans contributes to bacterial survival, through signaling for biofilm formation as well as regulation of stress related genes, growth under iron starvation, and antibiotic resistance.[14].[47] A study conducted by Santos et al. was the first to observe biofilms in animal reservoirs "presenting leptospiral renal carriage", and in their rat study system, L. interrogans biofilm formation was shown upon colonization in the renal area of these animals.[14] This study highlights the importance of the bacterial dependence on quorum sensing, as there was a positive correlation seen between the bacterial count present and biofilm formation.[14] Unlike other bacteria, L. interrogans lack the autoinducer-2 synthesizing machinery for quorum sensing, and use the S-adenosylhomocysteine nucleosidase, SAH, pathway.[47] Biofilm formation leads to the up-regulation of virulence-associated proteins as well as outer membrane proteins- supporting cell growth, as well as providing protection against environmental conditions that may be stressful, such as changes in pH, temperature, osmotic shock, and toxic compounds.[48][14]

-Olivia

Classification of LPS as an endotoxin-[49]

Hemolysin- exotoxin[49]


Vaccines against leptospirosis in dogs have been available in America since 2001; however, these vaccines are considered non-core vaccines.[50] Such vaccines are inactivated vaccines, reducing adverse reactions. The only vaccine currently recommended by experts is a quadrivalent vaccine containing L. interrogans serovars Canicola, Icterohaemorrhagiae, Grippotyphosa, and Pomona.[50] As this vaccine is serovar specific, ongoing research is being conducted in hopes to provide a vaccine that would be more protective, and a recent study conducted by Bouvet et al. shows promising protection of EURICAN® DAPPi-Lmulti against L. interrogans serovar Copenhageni, which they describe as a serovar of major medical importance.[51]

-Olivia

Morphology[edit]

L. interrogans cells are gram-negative, tightly coiled, motile spirochetes, with two periplasmic flagella. These flagella have polar insertions. The cells are thin, about 0.1 µm, and long, between 6-20 µm, with a corkscrew shaped body with extended hooked ends.These hooked ends often resemble a question mark, and this is where the name ‘interrogans’ comes from. The periplasmic flagella are crutial to the bacteria's ability to move and survive in specific host cells. The leptospires reveal two unique forms of movement, including translational and non translational.

Updated morphology section-Logan

The optimal growth of the obligate aerobe L. interrogans occurs in simple media that contain vitamins, salts, and specific long chain fatty acids.

-Metabolic information updated-Logan

Lead Section Draft:

Leptospira interrogans is a Gram-negative spirochaete bacterium, a member of the Spirochaetota, and causes severe mammalian infections.[52] As it is an obligate aerobe, requiring oxygen to grow, and lacks superoxide dismutase, SOD, enzymes, such as catalase must replace the SOD.[13][53][38] Unlike other bacteria, L. interrogans possess two periplasmic flagella, which enable motility through connective tissues, allowing close contact to the host cells.[38] Once in close proximity to host cells, some outer membrane proteins allow adherence to host cell’s surface molecules, adherence of L. interrogans to host cells initiates the infection process.[23] Infection is promoted through the production of virulence factors such as exotoxins including hemolysin proteins.[38]This species is pathogenic to some wild and domestic animals, including pet dogs. It can also spread to humans through abrasions on the skin, where infection can cause flu-like symptoms with kidney and liver damage.[54] Human infections are commonly spread by contact with contaminated water or soil, often through the urine of both wild and domestic animals.[54] Some populations of individuals are more susceptible to serious infection, including professions like farmers and veterinarians who work around animals.[19] L. interrogans is mainly found in tropical regions, where waste treatment is underdeveloped.[54] The bacterium exhibits two phases of infection including icteric or anicteric. The anicteric phase of infection is commonly known as phase 1 in which humans will exhibit fever, headache, and nausea, while the icteric phase or phase two includes more severe symptoms including hemorrhages and renal tubular failure.[55] The main ways for testing for the presence of the bacterium and diagnosing diseased humans include the microscopic agglutination test (MAT) and PCR.[5] Leptospirosis is commonly treated in humans by the antibiotics penicillin and doxycycline.[56]

L. interrogans contains two circular chromosomes.[52] Genes specifically encoding for long-chain fatty-acid utilization, the TCA cycle, and electron transport chain have been identified in L. interrogans.[2] The detection of such genes confirms the use of oxidative phosphorylation for ATP production from beta-oxidation of long chain fatty acids as the primary metabolic pathway of L. interrogans, as it has only one glucose uptake system, and uptake is limited.[2][57] A large amount of genes related to eukaryotic cell invasion, cell attachment, and motility have been discovered as well.[37][38][39]

There are more than 200 diverse pathogenic Leptospira serovars that make it challenging to develop an effective vaccine against leptospirosis in humans.[58] However, vaccines against leptospirosis in dogs have been available in America since 2001.[51] Such vaccines are inactivated vaccines, reducing adverse reactions.


^ lead introductory sentence was modeled from the wiki page S. aureus.

^ Summarizes all major points in the article without going too much in depth

^ All information included is also present in body of the article.

L. interrogans has only one glucose uptake system, known as the glucose sodium symporter. Although capable of glucose metabolism, the major energy and carbon source of this organism is the beta-oxidation of long chain fatty acids. It is yet to be found the reason for beta-oxidation preference, but Nascimento et al. suggest it is due to the limitations of only one uptake system.

-Olivia

This is the old lead draft- I didn't want to delete it completely.

Leptospira interrogans is a species of obligate aerobic spirochaete bacteria shaped like a common corkscrew with hooked ends. Leptospira is one of the genera of the spirochaete phylum that causes severe mammalian infections. This species is pathogenic to some wild and domestic animals, including pet dogs. It can also spread to humans through abrasions on the skin, where infection can cause flu-like symptoms with kidney and liver damage. Human infections are commonly spread by contact with contaminated water or soil, often through the urine of both wild and domestic animals. Some populations of individuals are more susseptible to serious infection, including professions like farmers and veterinarians who work around animals. L. interrogans is mainly found in tropical regions, where waste treatment is underdeveloped and temperature ranges are between 28-30 degrees Celsius. The bacterium exhibits two phases of infection including icteric or anicteric. The anicteric phase of infection is commonly known as phase 1 in which humans will exhibit fever, headache, and nausea, while the icteric phase or phase two includes more severe symptoms including hemorrhages and renal tubular failure. The main ways for testing for the presence of the bacterium and diagnosing diseased humans include the microscopic agglutination test (MAT) and PCR.The bacterium can live for weeks to months in ground or in water and can display many unique defense mechanisms to ensure its survival. L. interrogans contains many properties that ensure its optimal survival in specific conditions, including two periplasmic flagella for movement and mobility to more easily access and infect human and other mammialil tissue. In addition to its ability to infect hosts, the bacteria also exhibits the ability to use beta oxidation of long chain fatty acids for energy, in which includes oxygen and peroxides as its main terminal electron acceptors. L. interrogans contains two circular chromosomes, in which encode genes for evidence of its use of the TCA cycle and electron transport chain, revealing its use of oxidative phosphorylation for metabolism. The use of antimicrobials for treatment, including targeting certain aspects of the bacteria's physiology, can be affective in treatment of the disease. Leptospirosis is commonly treated in humans by the prescription of the antibiotics penicillin and doxycycline.


I was struggling with length of the lead, but this wiki article suggests 2-3 paragraphs based on our character count.

-Olivia

Taking our sandbox draft and converting it to what our Live Article would look like with all the information we've found- Olivia

Leptospira interrogans[edit]

Loganhardin/Leptospira interrogans
Scanning electron micrograph of Leptospira interrogans.
Scientific classification Edit this classification
Domain: Bacteria
Phylum: Spirochaetota
Class: Spirochaetia
Order: Leptospirales
Family: Leptospiraceae
Genus: Leptospira
Species:
L. interrogans
Binomial name
Leptospira interrogans
(Stimson 1907) Wenyon 1926 (Approved Lists 1980)

Leptospira interrogans is a Gram-negative spirochaete bacterium, a member of the Spirochaetota, and causes severe mammalian infections.[52] As it is an obligate aerobe, requiring oxygen to grow, and many serovars lack superoxide dismutase, SOD, enzymes such as catalase must replace the SOD.[13][53][38] Unlike other bacteria, L. interrogans possess two periplasmic flagella, which enable motility through connective tissues, allowing close contact to the host cells.[38] Once in close proximity to host cells, some outer membrane proteins allow adherence to host cell’s surface molecules, adherence of L. interrogans to host cells initiates the infection process.[23] Infection is promoted through the production of virulence factors such as exotoxins including hemolysin proteins.[38]This species is pathogenic to some wild and domestic animals, including pet dogs. It can also spread to humans through abrasions on the skin, where infection can cause flu-like symptoms with kidney and liver damage.[54] Human infections are commonly spread by contact with contaminated water or soil, often through the urine of both wild and domestic animals.[54] Some populations of individuals are more susceptible to serious infection, including professions like farmers and veterinarians who work around animals.[19] L. interrogans is mainly found in warmer tropical regions in the ranges of 28-30 degrees Celsius, specifically where waste treatment is inadequate. The bacteria can live for weeks to months in the ground or water.[54]

The bacterium exhibits two phases of infection including icteric and anicteric. The anicteric phase of infection is commonly known as phase 1 in which humans will exhibit fever, headache, and nausea, while the icteric phase or phase two includes more severe symptoms including hemorrhages and renal tubular failure.[55] The main ways for testing for the presence of the bacterium and diagnosing diseased humans include the microscopic agglutination test (MAT) and PCR.[5] Leptospirosis is commonly treated in humans by the antibiotics penicillin and doxycycline.[56]There are more than 200 diverse pathogenic Leptospira serovars that make it challenging to develop an effective vaccine against leptospirosis in humans.[58] However, vaccines against leptospirosis in dogs have been available in America since 2001.[51] Such vaccines are inactivated vaccines, reducing adverse reactions.

L. interrogans contains two circular chromosomes.[52] Genes specifically encoding for long-chain fatty-acid usage, the TCA cycle, and electron transport chain have been identified in L. interrogans.[2] The detection of such genes confirms the use of oxidative phosphorylation for ATP production from beta-oxidation of long chain fatty acids as the primary metabolic pathway of L. interrogans, as it has only one glucose uptake system, limiting its uptake.[2][57] A large amount of genes related to eukaryotic cell invasion, cell attachment, and motility have been discovered as well.[37][38][39]

Biology and Biochemistry[edit]

Morphology[edit]

L. interrogans cells are Gram-negative, tightly coiled, motile spirochetes, with two periplasmic flagella.[59] One flagellum is inserted at each end of the bacterium. The cells are thin, about 0.15 µm, and long, between 6-20 µm, with a corkscrew shaped body with spiral or hooked ends.[59] The hooked ends often resemble a question mark, and this is where the name ‘interrogans’ comes from.[60] The periplasmic flagella are crucial to the bacteria's ability to move and survive in specific host cells. The leptospires reveal two unique forms of movement, including translational and non translational.[61]

Metabolism/Physiology[edit]

L. interrogans displays neutralophilic properties, growing in a pH range of 7.2 - 7.6, with an optimal pH of 7.4. The bacteria also display mesophilic growth properties and grow at a temperature range of 28 ℃ to 30 ℃.[62][60] The optimal growth of the obligate aerobe L. interrogans occurs in simple media containing vitamins, salts, and specific long chain fatty acids.[61] Leptospira require ammonium salts as well as long-chain fatty acids for metabolism.[13]

L. interrogans has only one glucose uptake system, known as the glucose sodium symporter.[57] Although capable of glucose metabolism, the major energy and carbon source of this organism is the beta-oxidation of long chain fatty acids. The reason for beta-oxidation preference is yet to be found, but Nascimento et al. suggest it is due to the limitations of only having one uptake system.[63] Through naturally occurring phase interfaces or its growth media, L. interrogans must physically obtain the long chain fatty acids in order to further metabolize them as an energy source.[2] Unique to the metabolic characteristics of L. interrogans, long chain unsaturated fatty acids are required for the bacterium to grow, as saturated fatty acids can only be metabolized in its presence.[2] L. interrogans contains genes that code for the use of the TCA cycle in its metabolism, and its ATP production comes through oxidative phosphorylation.[2] Oxygen serves as the terminal electron acceptor in this beta-oxidation, further classifying this bacterium as an obligate aerobe.[13][53] Evidence has also shown that peroxides such as H2O2 can also serve as a terminal electron acceptor, with catalase activity needed for it to survive in vivo.[2]

Iron is a growth requirement for L. interrogans as it allows for various physiological processes to occur such as DNA replication, metabolism, and transcription.[43] For disease pathogenesis, haem acts as a major iron source.[44] Catabolism of haem is regulated by hmuO, a haem oxygenase.[46] However, L. interrogans is capable of de novo synthesis of haem as well.[45] Biosynthesis of haem is regulated by the hemA operon, which is comprised of the following genes hemA/C/D/B/L/E/N/G.[46] Due to the locations of sigma factor binding sites and HemR boxes (a HemR-binding DNA motif), HemR, a two-component system, serves a dual function in the simultaneous repression and activation of hmuO and hemA promoters to control catabolism and biosynthesis of haem.[46]

Genomics[edit]

Leptospira interrogans serovar Lai circular chromosomes [64]

The L. interrogans genome consists of two circular chromosomes composed of a total of almost 4.7 Mbp.[52] The larger chromosome has a total genome of 4.3 Mbp, and the smaller chromosome has a size of 350-360 Kbp. It has a G+C content of 35-36% and contains 3,700-4,700 protein-coding genes, depending on the strain.[57] Approximately 4,360 genes are on CI, and 367 are on CII. Only 37 of these genes encode for transfer RNAs, and the bacteria also has a low number of rRNA encoding genes. All rRNA and tRNA genes are located on CI, along with most genes related to growth. Genes specifically encoding for long-chain fatty-acid usage, the TCA cycle, and electron transport chain have also been identified in L. interrogans. The detection of such genes confirms the use of oxidative phosphorylation as the primary metabolic pathway of L. interrogans. A large amount of genes related to eukaryotic cell invasion, cell attachment, and motility have been discovered. L. interrogans also has a complex set of genes associated with chemotaxis, more so than other pathogenic bacteria such as B. burgdorferi and T. palladium. Such genes enable L. interrogans to be such a successful pathogen.[52]

To have the energy necessary for growth and to take over host functions, the bacterium employs methods such as oxidative stress.[16] Stress responses seen in L. interrogans include the up-regulation expression of genes encoding proteins such as chaperone proteins including clpA, heat shock proteins including GroEL, and endoflagellar proteins including flgA.[25]

As L. interrogans is an obligate aerobe, reactive oxygen species (ROS) must be avoided during metabolism. Many L. interrogans serovars lack superoxide dismutase, SOD, which functions to convert the reactive oxygen ion superoxide into oxygen and hydrogen peroxide; therefore, other enzymes must replace this missing SOD.[38] Among these enzymes that replace SOD are catalase, thiol peroxidase, and glutathione peroxidase.[38] The perRA and perRB genes encode peroxide responsive regulators, and these regulators promote host adaptation as they contain approximately 17 genes which aid in signaling.[24]

Antibiotic resistance genes have been discovered within multiple serovars of L. interrogans. These genes contribute to mechanisms of antibiotic resistance by altering the target, degrading the antibiotic, modifying the antibiotic, and pumping the antibiotic out of the cell.[33][40] For example, within the Lai serovar, such genes identified include vancomycin resistance proteins, acriflavine resistance proteins, and bacitracin resistance proteins.[38]

Genomic flexibility, as described by Ramli et al., is seen by serovars of L. interrogans possessing mobile elements.[37] Such mobile elements include plasmids, insertion sequences, and prophages.[37] Transposable elements have also been found in L. interrogans. For example, the Himar1 mariner transposon leads to efficient mutagenesis in L. interrogans.[41] This mutagenesis is deemed efficient as it occurs without specific requirements for recipient strains, such as the requirement of co-factors for insertion into a chromosome.[42]

Molecular pathogenesis[edit]

Adherence of L. interrogans to host cells initiates the infection process.[38] Alpha-like integrin proteins, Lig (leptospira immunoglobulin-like) proteins, and fibronectin-binding proteins (cadF), recognize ligands on the host cell surface, mediate host cell entry, and guide binding respectively.[38] Prior to adherence though, mobility plays a vital role as a virulence factor.[38] Unlike other bacteria, L. interrogans possess two periplasmic flagella, which enable motility through connective tissues, allowing close contact to host cells.[38] Once in close proximity to host cells, some outer membrane proteins, such as OmpL1, allow adherence to host cell's surface molecules, aiding in the infection process of L. interrogans .[23] One study suggests that lipL32, another major protein in L. interrogans aids in virulence as well, as mutants led to quicker onset of clinical signs of leptospirosis.[39] Although, there is doubt regarding where this protein is located, one study suggests that it is a subsurface membrane lipoprotein on the inner leaflet of the outer membrane.[8] Utilizing Molecular Koch's Postulates, the loa22 gene has been classified as a virulence factor as well as it enables adherence to host cells.[4][65]

Once attachment has been successful, enzymes are released to degrade the host cell's membranes. Among these enzymes include phospholipase A1 and lysophospholipase, which cleave triglyceride molecules into fragments and degrade matrix proteins for invasion respectively.[38] In addition to these enzymes, hemolysin proteins, exotoxins, aid in pore-forming, and the creation of these transmembrane channels created in the host cells result in their damage.[38]

L. interrogans utilize the SAH pathway for quorum sensing. This quorum sensing leads to biofilm formation- which supports cell growth and aids in protection against environmental conditions that may be stressful.

Quorum sensing conducted by L. interrogans contributes to bacterial survival through signaling for biofilm formation as well as regulation of stress related genes, growth under iron starvation, and antibiotic resistance.[14][47] A study conducted by Santos et al. was the first to observe biofilms in animal reservoirs "presenting leptospiral renal carriage", and in their rat study system, L. interrogans biofilm formation was shown upon colonization in the renal area of these animals.[14] This study highlights the importance of the bacterial dependence on quorum sensing, as there was a positive correlation seen between the bacterial count present and biofilm formation.[14] Unlike other bacteria, L. interrogans lack the autoinducer-2 synthesizing machinery for quorum sensing, and use the S-adenosylhomocysteine nucleosidase, SAH, pathway.[47] Biofilm formation leads to the up-regulation of virulence-associated proteins as well as outer membrane proteins- supporting cell growth, as well as providing protection against environmental conditions that may be stressful, such as changes in pH, temperature, osmotic shock, and toxic compounds.[48][14]

The integration of bacteriophage genetic information into bacterial chromosomes provides bacteria with beneficial genes, such as antibiotic resistance genes, influencing the bacteria's fitness.

Virulence is also related to the leptospiral lipopolysaccharide, LPS, an endotoxin, which is known to uniquely activate macrophages in response to infection.[52] The bacterial chaperone ClpB is a major driver in the overall virulence of L. interrogans aiding in overall survival inside a host, controlling stress response, as well as a unique role of protein disaggregation, contributing to increased virulence and pathogenicity.[16]L. interrogans also has a rather complex chemotaxis system compared to other pathogenic microbes, contributing to its effectiveness as a pathogen.

Following genome sequencing, it was discovered that prophages, such as TA-TA and TG-CA, have been identified in L. interrogans.[26] Prophages play a vital role in virulence as they can provide the bacteria with beneficial genes, such as antibiotic resistance genes.[27][28]

Environment[edit]

L. interrogans are host-associated bacteria, and most infections are found in tropical regions. In the host environment, L. interrogans are first found in the blood and subsequently moves on to infect several organs. In particular, L. interrogans cells survive and multiply at an optimal rate in the kidneys. Due to translocation characteristics, it has been shown that it does not stay within animal cells during the infection cycle.[17]A characteristic of L. interrogans is that it possesses no observable secretion abilities despite residing extracellularly.[17] The pathogen mostly spreads through the bodily fluids of infected animals.[53] Rats are the primary carrier of leptospirosis but do not present any symptoms, transmitting the pathogen through urine, which can persist in freshwater.[66] The pathogen can then enter the body of a new host through the skin and mucous membranes, as well as through the consumption of contaminated waters.[53] Leptospira often enter the body through open cuts and other wounds, though they are unable to pass through an intact skin barrier.[66] Infected wild and domestic animals can continue to excrete the bacteria into the environment for several years, and the bacteria can survive in soil and water for months at a time.[54]

Persons at risk of becoming infected with leptospirosis are those living under conditions where water and soil conditions may be contaminated with the urine of infected animals. [18] Occupations at higher risks of becoming infected include those such as farmers, veterinarians, and military personnel who regularly work outdoors in fields or with animals. [19]

The risk of becoming infected is increased following hurricanes and heavy storms, as soil containing animal urine can runoff and contaminate floodwater. As a way to prevent infection, the CDC recommends covering wounds with waterproof bandages to seal out possibly contaminated water and wearing waterproof protective clothing.[67]

Disease[edit]

For the disease, see Leptospirosis.

Humans[edit]

In humans, symptoms caused by L. interrogans are biphasic, icteric or anicteric. The icteric form is also known as Weil’s disease.[55] It has been shown in studies that L. interrogans may damage the endothelial cell lining of various vessels and organs, allowing them to leak and further spread the bacteria to other parts of the body.[15] Symptoms can appear anywhere between 2 to 4 weeks after exposure. Phase 1 of infection is anicteric, and symptoms include fever, chills, headache, muscle aches, vomiting and diarrhea. Roughly 90% of infectious cases in humans will only consist of this phase; however, it is possible for the disease to progress into phase 2, known as the icteric phase. Symptoms of the icteric phase include petechiae, hepatomegaly, jaundice, renal tubular damage, hemorrhages, and subsequent renal insufficiency.[55] Leptospirosis is treated with the antibiotics doxycycline and penicillin.[54]

There are more than 200 diverse pathogenic Leptospira serovars that make it challenging to develop an effective vaccine.[58] However, vaccines for the serovars known as Hardjo, Pomona, Canicola, Grippotyphosa and Icterohaemorrhagiae have been developed. Unfortunately, these vaccines display suboptimal protection, need frequent booster doses, and are specific to certain serovars.[58]

Dogs[edit]

Leptospirosis in canines can be divided into the four categories of reproductive, icteric, hemorrhagic, and uremic. Reproductive leptospirosis results in the premature birth of offspring or abortion, and uremic leptospirosis is referred to as Stuttgart disease.[20]L. interrogans triggers a highly inflammatory response in infected dogs. This inflammatory response results in the high expression of tumor necrosis factor alpha, referred to as TNF-α, in the uterine tissue of infected dogs. Interleukin-1β and interleukein-6 also exhibit increased levels of expression upon infection. Furthermore, L. interrogans is proven to result in the down-regulation of extracellular matrix (ECM) mRNA and proteins. These factors are likely correlated with the high susceptibility of canines to leptospirosis.[20]

Vaccines against leptospirosis in dogs have been available in America since 2001; however, these vaccines are considered non-core vaccines.[50] Such vaccines are inactivated vaccines, reducing adverse reactions.[50] The only vaccine currently recommended by experts is a quadrivalent vaccine containing L. interrogans serovars Canicola, Icterohaemorrhagiae, Grippotyphosa, and Pomona.[50] As this vaccine is serovar specific, ongoing research is being conducted in hopes to provide a vaccine that would be more protective, and a recent study conducted by Bouvet et al. shows promising protection of EURICAN® DAPPi-Lmulti against L. interrogans serovar Copenhageni, which they describe as a serovar of major medical importance.[51]

Classical diagnosis[edit]

Currently, in best practices, the disease is diagnosed by a microscopic agglutination test, MAT, but this test is unable to detect the disease during its early stages.[5] Combining diagnostic tests with a MAT, such as a PCR test, improves the diagnosis of the disease during its early stages.[6] Recent studies are improving the PCR tests in hopes to increase the diagnostic accuracy by utilizing tests that target 16S ribosomal RNA and lipl32 genes.[7]

Utilizing 16s rRNA PCR testing is beneficial as treatment with antibiotics makes it difficult to detect infection through bacteria culture testing.[11] In a study conducted by Boonsilp et al., it was found that a proportion of patients who were found to be negative utilizing bacteria culture testing were found to be positive through 16S rRNA PCR testing, which the authors contribute to the “ready availability of over the counter antibiotics.”[11] Thus, utilizing 16S rRNA gene sequencing is advantageous as it is culture-independent. Additionally, culturing L. interrogans is very difficult as they are slow growing, with an average generation time between 15-23 hours, so observing positive cultural growth may take several weeks following the collection of a culture, typically up to three months.[12]

Treatment[edit]

Disk diffusion tests are utilized to measure the effectiveness of varying antimicrobials. On the Petri dish on the left, the antibiotic disks are placed in agar media. After incubation, if the antimicrobial was effective in inhibiting bacterial growth, a zone of inhibition is seen, as depicted by disk "C" on the Petri dish on the right.

Before the development of LVW, Leptospira Vanaporn Wuthiekanun agar, there was no accepted standard method of testing the activity of antibiotic agents against L. interrogans. This is because the LVW agar is solid, not a liquid or semisolid medium as was used to culture L. interrogans previously.[29] This solid agar allows for disk diffusion testing of L. interrogans to be conducted against several antimicrobials.[30] In a study conducted by Wuthiekanun et al. seven L. interrogans serovars were grown on LVW agar plates and disk diffusion tests were conducted to test the susceptibility of the bacteria against several antimicrobials. [31] Susceptibility is calculated by using a ruler to measure the sizes of zones of inhibition, which are diameters around the disks infused with antimicrobials in which bacteria are unable to grow due to its presence. These measured diameters are then compared to a guidelines chart published by the Clinical and Laboratory Standards Institute. For each antimicrobial, it is determined whether the zone size is susceptible, intermediate, or resistant. [32] They found that all L. interrogans serovars were susceptible to the following antimicrobials: amoxicillin/clavulanic acid, amoxicillin, azithromycin, cefoxitin, ceftazidime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin, doripenem, doxycycline, gentamicin, linezolid, nitrofurantoin, penicillin, piperacillin/tazobactam, and tetracycline.[31] All serovars were found to be resistant to the following four antimicrobials, fosfomycin, nalidixic acid, rifampicin, and trimethoprim/sulfamethoxazole.[31]

Antimicrobials target specific aspects of a microbe's physiology. Such targets include the cell wall, DNA synthesis, RNA synthesis, protein synthesis, and metabolism.[33] Leptospirosis is commonly treated with the antibiotics penicillin and doxycycline.[56] Penicillin belongs to a class of antibiotics known as Beta-lactam antibiotics, which target the cell wall.[33] Beta-lactam antibiotics inhibit bacterial growth by interfering with peptidoglycan synthesis.[34] The binding targets of Beta-lactams are known as penicillin-binding proteins, PBPs. PBP enzymes including transpeptidase and transglycosylase are inhibited by the beta-lactam, preventing cross-linking of peptidoglycan peptides, leading to cell death.[35] Specifically in L. interrogans, the ponA and pbpB genes encode PBPs 1 and 3. Doxycycline belongs to a class of antibiotics known as Tetracyclines, which target protein synthesis. Tetracyclines block the binding of charged tRNAs to the A site of the ribosome.[33] Specifically, this antimicrobial affects the 30S subunit.

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