Streptobacillus Moniliformis

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1. Classification

a. Higher order taxa

The scientific classification for S. moniliformis is as followed, according to NCBI [1]: Domain - Bacteria Phylum - Fusobacteria Class - Fusobacteriaceae Order - Leptotrichiaceae Genus - Streptobacillus Species - Moniliformis

2. Introduction

The bacterium Streptobacillus moniliformis is a Gram-negative bacterium known for causing RBF (Rat Bite Fever) in humans. RBF is a zoonotic disease typically caused by direct contact with an infected rodent, such as via a rat bite (2), but it can also be contracted by indirect contact with an infected rodent through consumption of contaminants (Haverhill fever) (3). When humans are infected with S. moniliformis, the distinguishable symptoms consist of high fevers, rashes, joint and muscle pain, nausea, vomiting, and headaches (2). Children are the main population that is affected by this disease, due to the increase in children owning pets such as mice, rats, guinea pigs, hamsters, etc. (4). RBF is not well known in the United States, so data on this disease is limited (4). With increased crowding in cities where wild rodents tend to thrive, coupled with the increase in children owning rodents, people may be more susceptible to S. moniliformis than they were in the past (5). Current research focuses on advancements in detection and identification methods (2).

3. History

S. moniliformis was first isolated from the blood of a patient who had previously been bitten by a rat in 1914. It was then given one of its first names, Streptothrix muris ratti (6). In 1925, the bacterium attained its current name, Streptobacillus moniliformis (7). S. moniliformis has also been known as “Haverhillia multiformis”, which was named after a 1926 outbreak in Haverhill, MA that caused Haverhill fever, which is a form of RBF (8).

4. Morphology

S. moniliformis are Gram-negative bacteria that are rod-shaped (bacillus), non-encapsulated, non-spore forming, and are susceptible to decolorization by acids during staining (9). Under the microscope, S. moniliformis are often described as “string of beads” or a necklace, as the cells can be arranged in chains (filamentous) or clumps (10). The bacteria have a highly variable appearance (pleomorphic) because they often vary in size and shape. For instance, they can be as small as 0.1 μm to 3.5 μm and have been observed to have a spindle-like shape (fusiform) or long strand that resembles hair (10). S. moniliformis grows best on supplemented anaerobic blood agar and serum supplemented thioglycolate broth, on which it forms small gray-white colonies with adjacent pinpoint colonies on the former and loose, fluffy colonies in the latter (11).

5. Genome structure

The genome of S. moniliformis consists of 1,673,280 base pairs and is arranged in a single circular chromosome with one plasmid. 93.04% of the genome is coding and 26.28% of the genome consists of G+C bases (12). A total of 1,566 genes have been identified, with 1,511 being protein-coding genes, but only 67.31% of the genes have been predicted to have functions like translation of ribosomal structure, carbohydrate transport and metabolism, and cell membrane biogenesis (12). There have only been 55 observed RNA genes (12). Additionally, there has been one CRISPR repeat observed (12). It is unclear whether there are reported genes involved in pathogenesis (12).

6. Metabolic processes

S. moniliformis is a chemoheterotroph, using carbohydrates as an energy source, and monosaccharides and starch as carbon sources (12). The bacterium does not produce catalase or oxidase enzymes, suggesting that the bacterium uses fermentation for metabolism. The bacterium produces acid from metabolism of glucose, fructose, maltose, and starch, but no gas (12). There is disagreement regarding the oxygen requirements of the bacterium: S. moniliformis has been classified as a facultative anaerobe (13) and a microaerophile (14), while S. moniliformis isolated from guinea pigs specifically has been shown to behave as an obligate anaerobe (15).

7. Ecology

S. moniliformis survives in mammalian hosts. Rats are the most common carriers of S. moniliformis and harbor the bacteria in their upper respiratory tract (13). S. moniliformis has low pathogenicity in rats (13). Mice often harbor the bacterium and experience infection symptoms, such as enlargement of the lymph nodes and formation of small abscesses (13, 14). S. moniliformis in guinea pigs caused similar clinical symptoms as those in mice, such as lymph node enlargement (13). There have also been cases of S. moniliformis colonization in gerbils, ferrets, cats, dogs, turkeys, nonhuman primates, and koalas (13, 14). Most S. moniliformis cases have been reported from the United States, yet the bacterium is found worldwide, including many European countries, Australia, Canada, Mexico, Brazil and Paraguay. Few cases have been reported from Africa and Asia (14). Furthermore, there have been conflicting findings regarding the oxygen requirements of the bacterium, as one study stating that the bacterium is a facultative anaerobe while another study stating that it is a microaerophile, necessitating further research (13, 14).

8. Host Range and Susceptibility

S. moniliformis is able to infect all humans, however, the highest number of RBF cases are reported in children and young adults (4). Children account for over 50% of RBF cases in the United States (14). Older adults (greater than or equal to the age of 60) who are suffering with RBF stay at hospitals for longer periods of time in comparison to children and young adults, although older adults have lower rates of hospitalization (4). RBF hospitalization also differs by race: White populations have similar rates of hospitalization, but the Black and Hispanic population vary in rates of hospitalization. 85% of people infected with RBF live in an urban setting (4).

9. Transmission

Typically, Streptobacillus moniliformis is spread through bites from rats, leading to the nickname of RBF (16). It is also possible to become infected due to rat handling (2) or intake of contaminated substances from rats, such as food, drinking water, or feces (17). Haverhill fever is a term used to describe RBF contracted by such indirect contact (3). The speed of infectivity is not entirely understood, making infection rate difficult to assess. Symptoms appear between 3-21 days after infection, yet most people start showing symptoms 3-10 days after being infected (4).

10. Pathology

The most common symptoms of RBF observed in humans consist of high fever, rashes, joint and muscle pain, nausea, vomiting, and headaches (2). Haverhill fever presents with more severe gastrointestinal symptoms (3). Infection may lead to bacterial endocarditis (inflammation of the inner lining of the heart), pericarditis (inflammation of the pericardium), bronchitis (inflammation of the lining of the bronchial tubes), and persistent arthritis (swelling/tenderness of the joint). Children and infants who have been infected commonly experience anemia, weight loss, and diarrhea (2). While other symptoms have been observed, such as signs of pneumonia (17), they seem to be on an individual basis and not found in most cases. If left untreated in infants or those with pre-existing heart disease, RBF is likely to prove fatal (2).

11. Mechanism of Virulence

In cases of experimental infection in mice, S. moniliformis has resulted in arthritis in multiple joints. This begins with a pus that contains a large amount of fibrin forming in the joint space and nearby periosteum of the bones within the first 24 hours following infection (18). On day 4, there is the appearance of a macrophage immune response, then on day 7, there is formation of pus and necrosis near skeletal muscle within the joint (18). After two weeks, there is inflammation of the periosteum of the bone’s connective tissue, followed by proliferation of fibrous connective tissue at week 3 (18). While these are the observed manifestations of S. moniliformis causing arthritis, the causality of other symptoms is uncertain. Although S. moniliformis virulence is well known, the designated virulence-associated gene has not been identified in the most current complete genome sequence for S. moniliformis (12).

12. Diagnosis and Treatment

Culture isolation of S. moniliformis is performed to diagnose a patient with RBF (4). It is difficult to isolate and identify the bacteria because it requires a nutrient-rich blood environment. Nutrient-rich blood culture bottles contain sodium polyanethol sulfonate which make bacterial growth difficult (19). Gram stain identification is used as a preliminary diagnosis if there is no positive culture (4). Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is also used to identify S. moniliformis (2). However, this method requires the isolation and cultivation of the bacterium. MALDI-TOF MS takes an extensive amount of time which delays treatment and allows further deterioration of the patient (20). PCR testing is an effective and preferred method to identify S. moniliformis, particularly in animals. PCR testing is difficult to accurately perform due to challenges of culturing S. moniliformis (20). False positives have been shown to occur, likely due to the presence of the bacterium Leptotrichia sp., or a related species (20). A qPCR assay identified the grpE gene as an indicator for the Streptobacillus genus and the rpiL gene as an indicator of S. moniliformis, allowing for a clear determination of the bacterium in a host (2). DNA sequencing has also been used to diagnose S. moniliformis infection in humans (21). The usual treatment for RBF is treating the patient with antibiotics, such as penicillin (4). S. moniliformis is susceptible to all β-lactam antibiotics (9). One case study reported that the first recorded HIV-positive patient diagnosed with RBF had their symptoms resolved with an antibiotic cocktail of ceftriaxone, gentamicin, and penicillin (22).

13. Current Research

The goal of current research on S. moniliformis is to find better ways to identify and detect the pathogen in a clinical setting. In the past, clinical detection of S. moniliformis from blood samples was challenging, as the molecule sodium polyanethol sulfonate limited the growth of the bacterium when blood samples were obtained (23). Moreover, S. moniliformis needs selective requirements to grow, which causes difficulty in PCR detection (24). Fortunately, S. moniliformis and other rare pathogenic bacteria can now be detected using metagenomic next-generation sequencing (25). One specific case in China was able to diagnose a patient early enough to provide effective treatment of RBF for a patient due to a rapid result by mNGS (26). In 2021, researchers were able to determine a quick solution for genetically identifying S. moniliformis. Using a qPCR assay, presence of the grpE gene signifies a member of the Streptobacillus genus and presence of the rpiL gene indicates S. moniliformis (2). Development of this fast identification method allows for RBF patients to be treated before further deterioration.

14. References

[1][Schoch CL, et al. NCBI Taxonomy: a comprehensive update on curation, resources and tools. Database (Oxford). 2020.]

[2][Kelly, A. J., M. L. Ivey, C. A. Gulvik, B. W. Humrighouse, and J. R. McQuiston. 2021. A real-time multiplex PCR assay for detection of the causative agents of rat bite fever, Streptobacillus moniliformis and zoonotic Streptobacillus species. Diagnostic Microbiology and Infectious Disease 100 (2):1-6.]

[3][Chamberlain, N. (November 20, 2014). Rat Bite Fever. A.T. Still University. Retrieved November 20, 2021, from]

[4][Kache, P. A., M. K. Person, S. M. Seeman, J. R. McQuiston, J. McCollum, and R. M. Traxler . 2020 Rat-Bite Fever in the United States: An Analysis Using Multiple National Data Sources, 2001-2015. Infectious Disease Society of America 7 (6): 1-9.]

[5][Graves, M. H. and J. M Janda. 2001. Rat-bite fever (Streptobacillus moniliformis): A potential emerging disease. International Journal of Infectious Diseases 5: 151-155.]

[6][Schottmüller, H. 1914. Zur Ätiologie und Klinik der Bisskrankheit (Ratten-,Katzen-, Eichhörnchen-Bisskrankheit). Dermatol WOchenschr 58:77.]

[7][Levaditi C., S. Nicolau, and P. Poincloux.1925. Sur le rôle étiologique de Streptobacillus moniliformis (nov. spec.) dans l'érythème polymorphe aigu septicémique. C R Acad Sci 180: 1188-1190.]

[8][Parker F. J., and N. P. Hudson. 1926 The Etiology of Haverhill Fever (Erythema Arthriticum Epidemicum). Am. J. Path. 2:357]

[9][Eisenberg, T., N. Wener, N. Mauder, J. Rau, M. Contzen, T. Semmler, N. Hofmann, K. Aledelbi, and C. Ewers. 2015. Phenotypic and Genotypic Characteristics of Members of the Genus Streptobacillus. PLOS One 10 (8): 8-19.]

[10][Eisenberg T., C. Ewers, J. Rau, V. Akimkin, and W. Nicklas. 2016. Approved and novel strategies in diagnostics of rat bite fever and other Streptobacillus infections in humans and animals, Virulence, 7 (6): 630-648.]

[11][Pins, M. R., J. M. Holden, J. M. Yang, S. Madoff, and M. J. Ferraro. 1996. Isolation of Presumptive Streptobacillus moniliformis from Abscesses Associated with the Female Genital Tract. Clinical Infectious Diseases 22: 471-476.]

[12][Nolan, M., Gronow, S., Lapidus, A., Ivanova, N., Copeland, A., Lucas, S., Del Rio, T.G., Chen, F., Tice, H., Pitluck, S., et al. 2009. Complete genome sequence of Streptobacillus moniliformis type strain (9901). Stand Genomic Sci. 1 (3): 300-307.]

[13][Wullenweber, M. 1995. Streptobacillus moniliformis--a zoonotic pathogen. Taxonomic considerations, host species, diagnosis, therapy, geographical distribution. Laboratory Animals 29:1-15.]

[14][Elliot, S. P. 2007. Rat Bite Fever and Streptobacillus moniliformis. Clinical Microbiology Reviews 20 (1):13-22.]

[15][Smith, W. 1941. Cervical Abscesses of Guinea-Pigs. The Journal of Pathology and Bacteriology 53 (1):29-37.]

[16][Crofton, K. R., J. Ye, and E. P. Lesho. 2020. Severe Recurrent Streptobacillus Moniliformis Endocarditis in a Pregnant Woman, and Review of the Literature. Antimicrobial Resistance & Infection Control 9 (1): 1-119.]

[17][Onodera, H., H. Uekita, T. Watanabe, K. Taira, C. Watanabe, H. Saito, J. Seto, Y. Suzuki, and K. Imaoka. 2020. Rat-Bite Fever Due to Streptobacillus moniliformis in a Patient without Bite History: an Unexpected Cause of Consciousness Disturbance. Japanese Journal of Infectious Diseases 73 (1): 85-87.]

[18][Savage, N. L., G. N. Joiner, and D. W. Florey. 1981. Clinical, microbiological, and histological manifestations of Streptobacillus moniliformis-induced arthritis in mice. Infect. Immun. 34 (2):605-609.]

[19][Andre, J. M., A. M. Freydiere, Y. Benito, A. Rousson, S. Lansiaux, A. Kodjo, C. Mazzocchi, J. C. Berthier, F. Vandenesch, and D. Floret. 2005. Rat bite fever caused by Streptobacillus moniliformis in a child: human infection and rat carriage diagnosed by PCR. Journal of Clinical Pathology 58 (11): 1215–1216.]

[20][Boot, R., L. Van de Berg, F. A. G. Reubsaet, and M. J. Vlemminx. 2008. Positive Streptobacillus moniliformis PCR in guinea pigs likely due to Leptotrichia spp. Veterinary Microbiology 128:395-399.]

[21][Berger, C., M. Altwegg, A. Meyer, and D. Nadal. 2001. Broad Range Polymerase Chain Reaction for Diagnosis of Rat-Bite Fever Caused by Streptobacillus Moniliformis. The Pediatric Infectious Disease Journal 20 (12):1181-1182.]

[22][Rodorf, T., C. Zuger, R. Zbinden, A. von Graevenitz, and M. Pirovino. 2000. Streptobacillus moniliformis endocarditis in an HIV-positive patient. Infection 28(6): 393-394.]

[23][Lambe D, A. McPhedran, J. Mertz, P. Stewart. 1973. Streptobacillus moniliformis Isolated from a Case of Haverhill Fever: Biochemical Characterization and Inhibitory Effect of Sodium Polyanethol Sulfonate. American Journal of Clinical Pathology 60(6): 854–860.]

[24][Boot R, A. Oosterhuis, and H. C. Thuis. 2002. PCR for the detection of Streptobacillus moniliformis. Lab Animals 36:200-208.]

[25][Miao Q., Y. Ma, Q. Wang, J. Pan, Y. Zhang, W. Jin, Y. Yao, Y. Su, Y. Huang, M. Wang, B. Li, H. Li, C. Zhou, C Li, M. Ye, X. Xu, Y. Li, and B. Hu. 2018. Microbiological Diagnostic Performance of Metagenomic Next-generation Sequencing When Applied to Clinical Practice. Clinical Infectious Diseases, 67 (2): S231–S240.]

[26][Zhang, W. W., Y. B. Hu, G. X. He, Y. Zhou, and L. Hong. 2019. Rat bite fever caused by Streptobacillus moniliformis infection in a Chinese patient. BMC Infect Dis 19:637.]

Edited by [David Barnes], student of Jennifer Bhatnagar for BI 311 General Microbiology, 2021, Boston University.