Coxiella burnetii is an obligate intracellularbacterial pathogen, and is the causative agent of Q fever.[1] The genus Coxiella is morphologically similar to Rickettsia, but with a variety of physiological differences genetically classified as part of the class Gammaproteobacteria (and not Alphaproteobacteria, like Rickettsia). C. burnetii is a small Gram-negative, coccobacillary bacterium that is highly resistant to environmental stresses such as high temperature, osmotic pressure, and ultraviolet light. These characteristics are attributed to a small cell variant form of the organism that is part of a biphasic developmental cycle, including a more metabolically and replicatively active large cell variant form.[2] It can survive standard disinfectants, and is resistant to many other environmental changes like those presented in the phagolysosome.[3]
The causative agent of Q fever, Coxiella burnetti, was discovered in the 1930s through separate studies in Montana, United States, and in Queensland, Australia. The definitive descriptions of the pathogen were published in the late 1930s through studies on Q fever, by Edward Holbrook Derrick and Macfarlane Burnet in Australia, and by Herald Rea Cox and Gordon Davis at the Rocky Mountain Laboratory (RML) in the United States.[4]
The RML team proposed the name Rickettsia diaporica, derived from the Greek word for 'passing through,' referring to its filterable features. Around the same time, Edward Derrick suggested the name Rickettsia burnetii to recognize Macfarlane Burnet's contribution in identifying the organism as a Rickettsia.[5] Once it became clear that the species significantly diverged from other rickettsiae, it was reclassified as a new subgenus, Coxiella. In 1948 Cornelius B. Philip, another RML researcher, promoted it to full genus status as Coxiella burnetti, in honor of both Cox and Burnet.[6] Research in the 1960s–1970s by French Canadian-American microbiologist and virologistPaul Fiset was crucial in developing the first effective Q fever vaccine.[7]
Coxiella was difficult to study because it could not be reproduced outside a host. However, in 2009, researchers established an axenic culture technique, which opened a new useful way for the study of other pathogens.[8]
Pathogenesis
Immunohistochemical detection of C. burnetii in resected cardiac valve of a 60-year-old man with Q fever endocarditis, Cayenne, French Guiana, monoclonal antibody against C. burnetii and hematoxylin were used for staining: Original magnification ×50
Of the many C. burnetii strains, two of the most studied are the Nine Mile phase I and Priscilla phase I strain. In recent years, more strains have been studied. Nonetheless, it has been demonstrated that the Nine Mile strain is one of the most virulent strains of C. burnetti with as few as four organisms needed to cause infection. This is particularly relevant as murine rodents are poorly susceptible to C. burnetii, necessitating a higher dose and a more virulent dose to inoculate murine rodents for disease study.[9]
The ID50 (the dose needed to infect 50% of experimental subjects) is one via inhalation; i.e., inhalation of one organism will yield disease in 50% of the population. This is an extremely low infectious dose (only 1-10 organisms required), making C. burnetii one of the most infectious known organisms.[10][11] Disease occurs in two stages: an acute stage that presents with headaches, chills, and respiratory symptoms, and an insidious chronic stage.
C. burnettii infections begins within the alveoli. Upon inhalation, it targets alveolar macrophages and passively enters them via actin-dependent phagocytosis. After initial binding, it is suggested that C. burnetii enters phagocytotic cells via passive actin-dependent phagocytosis and enters non-professional phagocytes via an active zipper mechanism. C. burnetii exploits the αVβ3 integrin to enter using RAC1-dependent phagocytosis, which is believed to have evolved as a mechanism to avoid the induction of an inflammatory response.[12]
Following infection, C. burnetii has a biphasic developmental cycle, which consists of small cell variant and large cell variant morphological forms, which are both infectious. As the small cell variant is metabolically repressed and resistant to many environmental stressors, it is likely the form that initiates natural infections. Having entered a host cell, C. burnetii small cell variants transit through the phagolysosomal maturation pathway. In the first six hours post-infection, endosomes, autophagosomes, and lysosomes containing acid phosphatase fuse with the nascent phagosome to form early PV[clarification needed], which fosters the transition from small cell variant to large cell variant. C. burnetii is then metabolically activated and produces the T4SS to translocate effector proteins into the host cytoplasm. After 6 days, C. burnetii transitions back to small cell variant.[9][13]
While most infections clear up spontaneously, treatment with tetracycline or doxycycline appears to reduce the symptomatic duration and reduce the likelihood of chronic infection. A combination of erythromycin and rifampin is highly effective in curing the disease, and vaccination with Q-VAX vaccine (CSL) is effective for prevention of it.[citation needed]
The bacteria use a type IVB secretion system known as Icm/Dot (intracellular multiplication / defect in organelle trafficking genes) to inject over 100 effector proteins into the host. These effectors increase the bacteria's ability to survive and grow inside the host cell by modulating many host cell pathways, including blocking cell death, inhibiting immune reactions, and altering vesicle trafficking.[14][15][16] In Legionella pneumophila, a related Gammaproteobacterium which uses the same secretion system and also injects effectors, survival is enhanced because these proteins interfere with fusion of the bacteria-containing vacuole with the host's degradation endosomes.[17]
Prevalence
Coxiella burnetti is found commonly in domestic reservoirs such as sheep, goats, and cattle, and the microbe is spread to other organisms through the inhalation of contaminated aerosols. It presents asymptomatically in animals, and proves to cause chronic disease in nearby humans. The microbe is spread from domestic animals to human hosts during parturition or slaughter of the domestic animal.[citation needed]
Q fever is present in German human populations with 27-100 cases reported annually. It is estimated to affect 50 per every 100,000 inhabitants annually in France. The UK has faced 904 cases between 2000-2015, as well as major outbreaks in 2002 and 2007.[18] Coxiella burnetii has been observed with a greater prevalence in populations in close proximity to animals as well as homeless populations in Brazil.[19] In Algeria, residents of rural areas were at a three times higher risk for Coxiella burnetti infections compared to inhabitants of urban areas. [20]
Coxiella burnetti and bacteria similar to it were found in tick species that populate wildlife in South Korea.[21] The microbe has also been found in ticks that were collected from Churra Galega Mirandesa sheep in Portugal.[22]
Use as a biological weapon
The United States ended its biological warfare program in 1969. When it did, C. burnetii was one of seven agents it had standardized as biological weapons.[23] There are many unique aspects of C. burnetii that make it a desirable bioweapon. C. burnetii maintains an extremely low infectious dose, requiring only 1-10 organisms in order to cause infection in a human target.[24] A WHO study estimated that releasing 50kg of C. burnetti 2km upwind of a population of 500,000 could cause around 150 deaths with about 125,000 incapacitated by Q fever.[25] Q fever has an incubation period of 1-3 weeks in the body between the point of infection and when symptoms can arise. C. burnetii can also exist in two forms: a metabolically active large cell variant and a spore-like small cell variant. The small cell variant is able to persist in the environment without a host while still maintaining infectious capabilities for years. This small cell variant is small enough to be dispersed miles by wind.[26] Acute Q fever can manifest as low grade flu-like symptoms. However, if left untreated, Q fever can escalate into endocarditis, pregnancy complications and liver damage. While the mortality rate for Q fever is only around 0.5-1.5%, the bacteria can exist in the body for years and develop into chronic Q fever with more intense complications. Around 20% of those infected with Q fever will experience chronic fatigue and symptoms that can last years after the initial exposure to C. burnetii.[27]
At least 75[28] completely sequenced genomes of Coxiella burnetii strains exist,[29] which contain about 2.1 million base pairs of DNA each and encode around 2,100 open reading frames (ORFs), which are stretches of DNA that can be read to produce proteins; 746 (or about 35%) of these genes have no known function.
Recent advances in sequencing techniques, particularly selective whole genome amplification (SWGA), allowed for the recovery of even more C. burnetii genomes. These samples were found in clinical and environmental studies. In one study, researchers applied SWGA to environmental samples such as unpasteurized milk and goat vaginal swabs. The technique helped increase the amount of C. burnetii DNA found in the samples by up to 147 times more than before. This improvement dramatically increased bacterial reads and genome coverage from less than 1% of sequence reads to as high as 74%, providing enough genetic information to compare different strains and understand how they are related.[30] The ability to sequence C. burnetii even when it is present in very small amounts helps expand what we know about its genetic diversity and supports better tracking of how the bacteria spread and evolve.[citation needed]
In bacteria, molecules called small regulatory RNAs are activated during stress and virulence conditions. In Coxiella burnetii, several of these small RNAs (named CbSRs 1, 11, 12, and 14) are encoded within intergenic region (IGR), or the DNA between genes. CbSRs 2, 3, 4 and 9 are located complimentary to identified ORFs. The CbSRs are up-regulated during intracellular growth in host cells.[31]
All C. burnetii strains contain extra genetic material - either one of four large plasmids (QpH1, QpDG, QpRS, or QpDV) or a piece of DNA in the chromosome that originated from the QpRS plasmid. The QpH1 plasmid plays a key role in helping the bacteria survive inside host cells such as mouse macrophages[32] and Vero cells, although it is not needed for growth in artificial (axenic) culture. QpH1 also contains a toxin-antitoxin system,[33] which may help the plasmid remain stable in the bacteria. Among all of these plasmids, eight conserved genes produce proteins that the bacteria inject into the host cells via the secretion system.[33]
↑ Sankaran N (2000). "Coxiella burnetii". Microbes and people: an A-Z of microorganisms in our lives. Phoenix, Arizona: The Oryx Press. pp.72. ISBN1-57356-217-3. "In contrast to other rickettsiae, which are highly sensitive and easily killed by chemical disinfectants and changes in their surroundings, C. burnetii is highly resistant" & "Q fever". Centers for Disease Control and Prevention; National Center for Infectious Diseases; Division of Viral and Rickettsial Diseases; Viral and Rickettsial Zoonoses Branch. 2003-02-13. Retrieved 2006-05-24. "The organisms are resistant to heat, drying, and many common disinfectants."
↑ "Genome - NCBI". National Center for Biotechnology Information, U.S. National Library of Medicine. Archived from the original on 2011-11-28. Retrieved 1 January 2022.
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