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Rickettsia rickettsii is a Gram-negative, intracellular, coccobacillus bacterium that was first discovered in 1902. Having a reduced genome, the bacterium harvests nutrients from its host cell in order to carry out respiration, making it an organoheterotroph.[1] Maintenance of its genome is carried out through vertical gene transfer where specialization of the bacteria allows it to shuttle sugars directly into the TCA cycle.

Other characteristics of the bacteria include membrane proteins that are useful in the targeting of antibiotics and the identification of the strain. A capsule encircling the bacterium acts as both a defense mechanism in resisting phagocytosis and an advantage in physically attaching to host cells. Varying strains of R. rickettsii have different genotypes and phenotypes that alter the pathogenicity, virulence, and appearance of the bacteria.

R. rickettsii is the causative agent of Rocky Mountain Spotted Fever and is transferred to its host via a tick bite. It is one of the most pathogenic Rickettsia species and affects a large majority of the Western Hemisphere, most commonly the Americas. The pathogenic agent has been found on every continent, except Antarctica; however, Rocky Mountain Spotted Fever occurs mostly in North, Central, and South America. This prevalence is due to R. rickettsi thriving in warm, damp environments. These environments provide sufficient conditions for the amplification of the bacteria within a vertebrate host, such as a horse or a dog. The bacteria is transmitted through the vector, a tick, to a vertebrate host where it can then be amplified and passed on to a person, resulting in the zoonotic disease.

Headache, high fever, and spotted rash are some effects of the disease with more severe cases resulting in organ damage, coma, and death. Antibiotics, such as doxycycline, target the ribosome of R. Rickettsii in order to inhibit protein synthesis of the bacteria, providing a form of treatment for the disease.

Transmission cycle[edit][edit]

The most common hosts for the R. rickettsii bacteria are ticks. Ticks that carry R. rickettsia fall into the family of Ixodidae ticks, also known as "hard-bodied" ticks. Ticks are vectors, reservoirs, and amplifiers of this disease.

There are currently three known tick species that commonly carry R. rickettsii. The American Dog Tick (Dermacentor variabilis), mainly found in the eastern United States, is the most common vector for R. rickettsii. The Rocky Mountain Wood Tick (Dermacentor andersoni), found in the Rocky Mountain States, and the Brown Dog Tick (Rhipicephalus sanguine), found in select areas of the southern United States, are also known vectors of the pathogen.

Ticks can contract R. rickettsii by many means. First, an uninfected tick can become infected when feeding on the blood of an infected vertebrate host; such as a rabbit, during the larval or nymph stages, this mode of transmission is called transstadial transmission. Once a tick becomes infected with this pathogen, they are infected for life. Both the American Dog Tick and the Rocky Mountain Wood Tick serve as long-term reservoirs for Rickettsia rickettsii, in which the organism resides in the tick posterior diverticula of the midgut, the small intestine and the ovaries. In addition, an infected male tick can transmit the organism to an uninfected female during mating. However, this process is unlikely to play a major role in the maintenance of R. rickettsii within a population as females infected during mating have not been observed to produce infected offspring. Infected female ticks can transmit the infection to their offspring, in a process known as transovarian passage. Notably, R. rickettsii is inefficient at infecting the ovaries of adult female ticks, resulting in a lowered rate of vertical transmission.[2] Rickettsial colonization of the ovaries sees higher success when ticks obtain the pathogen as a larvae or nymph.[3] Reduced fecundity is also observed in ticks infected with R. rickettsii.[4] As a result of these limitations, long-term maintenance of R. rickettsii in populations of ticks relies mainly on horizontal transmission through the exchange of bacteria during feedings of infected hosts.[5][4]

Ecology[edit]

In addition to having vectors in the United States, R. Rickettsii commonly infect certain ticks in South America. The cayenne tick (Amblyomma cajennense) and the brown dog tick (Rhipicephalus sanguineus) are both common vectors found in South America. The yellow dog tick (Amblyomma aureolatum) is another vector that infects specific parts of Brazil. Infecting horses and capybaras, the cayenne tick turns vertebrate hosts into amplifier hosts of the bacteria. Other small rodent species serve as amplifier hosts in the United States and South America.

Specific requirements must be fulfilled when looking at vertebrate hosts to become an amplifier host for R. Rickettsii. First, there should be a large population of said host in the endemic area. Then, the host must be a primary host for the vector, so it can carry out its life cycle. Furthermore, the vertebrate host must be prone to infection from R. Rickettsii, and once inside of the vertebrate host, the bacteria must infect the host to a great enough degree that the host's blood will infect other vectors that attach to the host. Finally, the host should be apart of a prolific species, so that the species does not become nonimmune.[6]

Physiology[edit]

Metabolic Pathways[edit]

R. rickettsii are obligate intracellular bacteria, meaning they need a host cell in order to replicate and survive. This makes culturing and growing this bacteria difficult, as only living eukaryotic cells can be used to grow the bacteria.[7] This is due to the pathogen having many metabolic deficiencies and having to borrow metabolites from the host cell. R. rickettsii is unable to utilize glycolysis and the pentose phosphate pathway due to a reduced genome, and since these pathways are unusable, the bacterium must use the tricarboxylic acid cycle (TCA) as an alternative pathway. However, this can only be done through the use of the host cell's metabolites. This is possible because cell envelope glycoconjugates are synthesized using three particular sugars found in host cells, along with the other metabolites that are acquired from the host cell that will fuel the TCA.[1]

One of the metabolites that R. rickettsii uses from its host cell in order to synthesize peptidoglycan and lipopolysaccharides is a sugar called UDP-N-acetyl-α-d-glucosamine. Other metabolites that are needed for this cell to survive within the host cell are imported glutamine, glutamate, and malate, which are used to regulate the flow of acetyl-CoA, which is synthesized using pyruvate that the bacteria also takes from the host cell, into the TCA cycle. Overall, R. rickettsii has a genome that does not encode many of the enzymes and proteins that are required for several pathways, other than the TCA cycle, so this cells imports many of the intermediates, cofactors, and byproducts from the host cells metabolic pathways to use for their own benefit and synthesis of necessary structures and energy that the bacteria needs to survive.[1]

Morphology[edit]

R. rickettsii is a gram-negative bacterium, and it has many vital proteins within its cellular membranes. One of these cellular membrane proteins is YbgF, which is a protein that maintains the structure of the cellular membrane. This protein is found within both the inner and outer membranes along with another cellular membrane protein called TolC. TolC is a transport protein that connects to other transport proteins within the periplasmic space and inner membrane. These two proteins are believed to be associated with pathogenicity of this microbe and are specific points that antibodies can bind to in order to prevent the bacteria from interacting with host cells.[8]

R. rickettsii also has an outer layer or a "microcapsule", which acts similarly to the S-layer or slime layer of other bacteria. Experiments have been performed to determine the structure of this slime layer, and it was found to consist mostly of polysaccharides. It is also believed that this "microcapsule" contributes to mechanisms involving anti-phagocytosis and attachment to host cells.[9]

Genome and Phenotypes[edit]

R. rickettsii is an obligate intracellular bacterium that requires a host cell for reproduction; additionally, it is an alpha proteobacterium that belongs to the Rickettsiacea family. It has a genome that consists of about 1.27 Mbp with ~1,350 predicted genes, which is smaller compared to most other bacteria. This small genome size allows the bacteria to maintain an intracellular lifestyle with increased pathogenicity due to gene reduction.[10] It is maintained in its tick host by transovarial transmission. Furthermore, the ticks ensure the maintenance of vertical gene transfer of the spotted fever group.[10] The multiplication of R. rickettsii is by binary fission inside the cytosol.

R. rickettsii is apart of the spotted fever group. This subgroup contains genes that code for unique outer surface proteins and specific surface cell antigens. Additionally, this subgroup codes for citrate synthase, which involves the start of the Krebs cycle. By examining VNTR sites on the genome of the bacterium, lineages of R. rickettsii may be shared geographically across the Americas, including places like Arizona, Southern California, and Panama.[10]

There are many strains of R. rickettsii that have been discovered with key characteristics that differentiate them. R. rickettsii Sheila Smith is a virulent strain that causes spotted fever. Other strains of R. rickettsii, such as R. rickettsii Iowa, have a genomic structure consistent with an avirulent phenotype. A key feature allowing for differentiation is the rickettsial outer membrane protein, rOmpA and rOmpB  which contributes to the identification of R. rickettsii strains as virulent. The detection of single nucleotide polymorphisms (SNPs) are used to differentiate these strains.

A mutation found in R. rickettsii Iowa reflect biofilm phenotypes that indicate a difference in the release of LDH. This mutation switches base pair G to A in the A1G_06035 gene at 231 bps, resulting in a visual difference in the plaque of the Iowa strain. This visual change is due to the mutation affecting a relA/spoT protein in which the biofilms of the Iowa strain appear clear. The clear plaques are a result from an increased release of LDH, which in response, results in more cell destruction. Opaque-plaque variants tend to release less LDH, resulting in an opaque appearance due to the presence of cells. Production of LDH based on plaque variant indicate a difference in destructive ability where clear plaques cause more cell destruction in comparison to opaque plaques.[11][12]

Genomic Comparison of Strains[edit]

R. rickettsii has a relatively small genome; however, difference in gene expression between different strains of the bacteria can lead to differing functions of the bacteria. For instance, there are two major strains of R. rickettsii called the Iowa and the Sheila Smith strains. The Sheila Smith strain is a virulent strain, while the Iowa strain is an avirulent strain. Microarrays revealed that there were only four distinct differences in the gene expression of R. rickettsii; however, these four changes lead to complete differences in virulence, and thus the niche of the bacteria.[13]

Clinical manifestations[edit]

Virulence[edit][edit]

While humans are hosts for R. rickettsii, they do not contribute to rickettsial transmission. Rather, the pathogen is maintained through its vector: ticks. R. rickettsii invades the endothelial cells that line the blood vessels in the host's body. Increased permeability of vessels, microvascular hemorrhages, and necrosis can result from damage to the cells. The pathogen causes changes in the host cell cytoskeleton that induces phagocytosis, and R. rickettsii replicates further and infects other cells in the host's body. R. rickettsii's survival in immune system cells increases the pathogen's virulence in mammalian hosts.

Actin-Based Motility (ABM) is a virulence factor that allows for the pathogen to evade the host's immune cells and spread to neighboring cells. It is suggested that the Sca2 gene, which is an actin-polymerizing determinant, is a distinguishing factor for the Rickettsia family, as R. rickettsii mutants with a Sca2 transposon avoided autophagic processes. This leads to an increase in disease manifestation for the host.

R. rickettsii is also able to suppress immune responses in infected cells by creating proteins prior to cell entry. The first of these proteins are TS44 and Rickettsial ankyrin repeat protein 2 (RARP2). RARP2 mediates the fragmentation of TGN, or the trans-Golgi network, causing attenuation of vesicular transport and glycosylation defects in infected cells. There are two important proteins within the host cell that are affected by these glycosylation defects which are, TGN46 and major histocompatibility complex class 1 (MHC-I). MHC-I is an important protein for defending against pathogens as it is sent to the plasma membrane and functions as a antigen presenting complex. However, since RARP2 causes attenuation of vesicular transport, MHC-I is unable to be transported to the plasma membrane and the cell will not be able to protect against the R. rickettsii bacterial cells that try to infect host cells and thus the bacterial cells are able to avoid certain immune responses, increasing pathogen proliferation for the bacteria.[14]

The Centers for Disease Control and Prevention states that the diagnosis of Rocky Mountain Spotted Fever must be made based on the clinical signs and symptoms of the patient and then later be confirmed using specialized laboratory tests. However, the diagnosis of Rocky Mountain Spotted Fever is often misdiagnosed due to its non-specific onset. The majority of infections from R. rickettsii occur during the warmer months between April and September. Symptoms can take 1–2 days to 2 weeks to present themselves within the host. The diagnosis of RMSF is easier when there is a known history of a tick bite or if the rash is already apparent in the affected individual. If not treated properly, the illness may become serious, leading to hospitalization and possible fatality.

Signs and symptoms[edit]

During the initial stages of the disease, the infected person may experience headaches, muscle aches, chills, and high fever. Other early symptoms may include nausea, vomiting, loss of appetite, and conjunctival injection (red eyes). Most people infected by R. rickettsii develop a spotted rash, that begins to appear 2 to 4 days after the individual develops a fever. If left untreated, more severe symptoms may develop; these symptoms may include insomnia, compromised mental ability, coma, and damage to the heart, kidneys, liver, lungs, or additional organs.

The classic Rocky Mountain Spotted Fever rash occurs in about 90% of patients and develops 2 to 5 days after the onset of fever. The rash can differ greatly in appearance along the progress of the R. rickettsii infection. It is not itchy and starts out as flat pink macules located on the affected individual's hands, feet, arms, and legs. During the course of the disease, the rash may form petechiae and take on a more darkened reddish purple spotted appearance, signifying severe disease.

In rarer cases, patients may present with chest pain due to myocarditis. Additionally, rare symptoms include vision impairment and arthritis that may exist as chronic sequelae, lasting anywhere from 10 days to 4 years. Other chronic sequelae include some cases of neurological challenges, such as impaired speech, dysphagia, ataxia, memory loss, cortical blindness, and decreased attention span. Necrosis of skin is another rare case of sequelae.[15][16]

Severe Infections[edit]

Patients with severe infections may require hospitalization. The more severe symptoms occur later in response to thrombosis (blood clotting) caused by R. rickettsii targeting endothelial cells in vascular tissue. They may become hyponatremic, experience elevated liver enzymes, and other more pronounced symptoms. It is not uncommon for severe cases to involve respiratory system, central nervous system, gastrointestinal system, or renal system complications. In the case of meningoencephalitis, R. rickettsii causes cellular damage to brain tissue, resulting in inflammation. Additionally, acute respiratory distress syndrome and coagulopathy occur in cases that advance to severe stages of RMSF.[17] This disease is worst for elderly patients, males, African Americans, alcoholics, and patients with G6PD deficiency. The mortality rate for RMSF is 3 to 5 percent in treated cases, but 13 to 25 in untreated cases. Deaths usually are caused by heart and kidney failure.

I like how various populations are represented here.

Treatment[edit]

RMSF symptoms can vary from moderate to severe cases, and a delay in treatment is often associated with a higher case-fatality rate.[18] The most common and effective treatment for Rocky mountain spotted fever is the anti-microbial agent doxycycline.[19][20] This antibiotic acts as a bacteriostatic drug by inhibiting protein synthesis via blockage of the 30S ribosomal subunit.[21]

Other treatments with chloramphenicol, fluoroquinolones, and macrolides have been explored. However, treatment with only chloramphenicol compared to these treatments (tetracycline-class drugs only, both chloramphenicol and tetracycline-class drugs, and neither drug) was associated with a case-fatality rate three times higher.[18] Chloramphenicol, like doxycycline, also functions as a bacteriostatic drug, but it binds to the 50S ribosomal subunit in order to prevent protein synthesis. Macrolides also target the 50S subunit; however, they block the exit site for peptides while chloramphenicol blocks the aminoacyl-tRNA attachment site for transfer RNA.[1]

History[edit]

The once lethal infection has become curable due to the research done in recent years. Chloramphenicol and tetracycline-class drugs, like doxycycline, were first harnessed as treatment for RMSF in the late 1940s, but before their discovery, 1 in 5 infected patients died.[22] Treatment recommendations changed in the 1990s to support primary therapeutic use of tetracycline-class drugs. This coincided with a decrease in annual case-fatality rates (CFRs) from the 1980s on to the early 1990s.[22] The fatality rate has dropped to between 5 and 10% since then.[23]

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content is pretty relevant to the topic and up-to-date.

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References[edit]

  1. ^ a b c Driscoll, Timothy P.; Verhoeve, Victoria I.; Guillotte, Mark L.; Lehman, Stephanie S.; Rennoll, Sherri A.; Beier-Sexton, Magda; Rahman, M. Sayeedur; Azad, Abdu F.; Gillespie, Joseph J. (2017-09). "Wholly Rickettsia! Reconstructed Metabolic Profile of the Quintessential Bacterial Parasite of Eukaryotic Cells". mBio. 8 (5). doi:10.1128/mBio.00859-17. PMID 28951473. {{cite journal}}: Check date values in: |date= (help)
  2. ^ Burgdorfer, Willy; Brinton, Lyle P. (November 1975). "MECHANISMS OF TRANSOVARIAL INFECTION OF SPOTTED FEVER RICKETTSIAE IN TICKS". Annals of the New York Academy of Sciences. 266 (1).
  3. ^ Piranda, Eliane M; Faccini, João Luiz H; Pinter, Adriano; Pacheco, Richard C; Cançado, Paulo H D; Labruna, Marcelo B (January 24, 2011). "Experimental Infection of Rhipicephalus sanguineus Ticks with the Bacterium Rickettsia rickettsii, Using Experimentally Infected Dogs". Vector-Borne and Zoonotic Diseases. 11 (1).
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  11. ^ Nock, Adam M.; Clark, Tina R.; Hackstadt, Ted (2022-04-26). Roy, Craig R. (ed.). "Regulator of Actin-Based Motility (RoaM) Downregulates Actin Tail Formation by Rickettsia rickettsii and Is Negatively Selected in Mammalian Cell Culture". mBio. 13 (2). doi:10.1128/mbio.00353-22. ISSN 2150-7511. PMC 9040884. PMID 35285700.{{cite journal}}: CS1 maint: PMC format (link)
  12. ^ Clark, Tina R.; Ellison, Damon W.; Kleba, Betsy; Hackstadt, Ted (2011-04). Morrison, R. P. (ed.). "Complementation of Rickettsia rickettsii RelA/SpoT Restores a Nonlytic Plaque Phenotype". Infection and Immunity. 79 (4): 1631–1637. doi:10.1128/IAI.00048-11. ISSN 0019-9567. PMC 3067566. PMID 21300770. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  13. ^ Ellison, Damon W.; Clark, Tina R.; Sturdevant, Daniel E.; Virtaneva, Kimmo; Porcella, Stephen F.; Hackstadt, Ted (2008-02). "Genomic comparison of virulent Rickettsia rickettsii Sheila Smith and avirulent Rickettsia rickettsii Iowa". Infection and Immunity. 76 (2): 542–550. doi:10.1128/IAI.00952-07. ISSN 1098-5522. PMC 2223442. PMID 18025092. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Kellermann, Malte; Scharte, Felix; Hensel, Michael (2021-06-17). "Manipulation of Host Cell Organelles by Intracellular Pathogens". International Journal of Molecular Sciences. 22 (12): 6484. doi:10.3390/ijms22126484. ISSN 1422-0067. PMC 8235465. PMID 34204285.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Jay, Riley; Armstrong, PaigeA (2020). "Clinical characteristics of Rocky Mountain spotted fever in the United States: A literature review". Journal of Vector Borne Diseases. 57 (2): 114. doi:10.4103/0972-9062.310863. ISSN 0972-9062.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Doyle, Amy; Bhalla, Karan S.; Jones, James M.; Ennis, David M. (2006-10). "Myocardial Involvement in Rocky Mountain Spotted Fever: A Case Report and Review". The American Journal of the Medical Sciences. 332 (4): 208–210. doi:10.1097/00000441-200610000-00009. ISSN 0002-9629. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Drexler, Naomi (2020). "Persistent Sequelae of Rocky Mountain Spotted Fever: Clinical Evidence, Cost, and Public Health Implications for Arizona Tribal Communities". ProQuest. Retrieved February 29, 2024.
  18. ^ a b Botelho-Nevers, E.; Raoult, D. (2011-10-01). "Host, pathogen and treatment-related prognostic factors in rickettsioses". European Journal of Clinical Microbiology & Infectious Diseases. 30 (10): 1139–1150. doi:10.1007/s10096-011-1208-z. ISSN 1435-4373.
  19. ^ Breitschwerdt, E. B.; Papich, M. G.; Hegarty, B. C.; Gilger, B.; Hancock, S. I.; Davidson, M. G. (1999-04). "Efficacy of Doxycycline, Azithromycin, or Trovafloxacin for Treatment of Experimental Rocky Mountain Spotted Fever in Dogs". Antimicrobial Agents and Chemotherapy. 43 (4): 813–821. doi:10.1128/AAC.43.4.813. ISSN 0066-4804. PMC 89211. PMID 10103185. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  20. ^ Dantas-Torres, Filipe (2007-11). "Rocky Mountain spotted fever". The Lancet Infectious Diseases. 7 (11): 724–732. doi:10.1016/s1473-3099(07)70261-x. ISSN 1473-3099. {{cite journal}}: Check date values in: |date= (help)
  21. ^ Holmes, Natasha E.; Charles, Patrick G.P. (2009-01). "Safety and Efficacy Review of Doxycycline". Clinical Medicine. Therapeutics. 1: CMT.S2035. doi:10.4137/CMT.S2035. ISSN 1179-1713. {{cite journal}}: Check date values in: |date= (help)
  22. ^ a b Holman, Robert C.; Paddock, Christopher D.; Curns, Aaron T.; Krebs, John W.; McQuiston, Jennifer H.; Childs, James E. (2001-12). "Analysis of Risk Factors for Fatal Rocky Mountain Spotted Fever: Evidence for Superiority of Tetracyclines for Therapy". The Journal of Infectious Diseases. 184 (11): 1437–1444. doi:10.1086/324372. ISSN 0022-1899. {{cite journal}}: Check date values in: |date= (help); no-break space character in |first2= at position 12 (help); no-break space character in |first3= at position 6 (help); no-break space character in |first4= at position 5 (help); no-break space character in |first5= at position 9 (help); no-break space character in |first6= at position 6 (help); no-break space character in |first= at position 7 (help)
  23. ^ CDC (2022-08-15). "Epidemiology and statistics of spotted fever rickettsioses". Centers for Disease Control and Prevention. Retrieved 2023-10-31.
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