Rickettsia rickettsii is a Gram-negative, intracellular, cocco-bacillus bacterium that was first discovered in 1896. Having a reduced genome, the bacterium harvests nutrients from its host cell to carry out respiration, making it an organo-heterotroph. Maintenance of its genome is carried out through vertical gene transfer where specialization of the bacterium allows it to shuttle host sugars directly into its tricarboxylic acid (TCA) cycle.
Other characteristics of the bacteria include membrane proteins that are useful in the identification of R. rickettsii strains and useful in targeting from antibiotics. A capsule encircling the bacterium allows for attachment to host cells and additionally acts as a defense mechanism for resisting phagocytosis. Varying strains of R. rickettsii have different genotypes and phenotypes that alter the pathogenicity, virulence, and the 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. These environments provide sufficient conditions for the amplification of the bacteria within a vertebrate host, such as a horse or dog. The bacteria are transmitted through a vector, such as 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 and coma. 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.
Physiology
Metabolic pathways
R. rickettsii are obligate intracellular bacteria, meaning they need a host cell in order to replicate and survive. In fact, no glycolytic enzymes for the breakdown of intact glucose remain in R. rickettsii's genome. It is theorized that while R. rickettsii once possessed complete, complex metabolic pathways that allowed it to survive outside a host, evolutionary pressures caused progressive genomic reduction that now limits metabolism to the tricarboxylic acid cycle (TCA). Remnants of these lost metabolic pathways can be seen in analysis of R. rickettsii's genome, which contain some identified remnant enzymes of pathways that remain unfunctional in vivo.
Pathophysiology
thumb|Rickettsia rickettsii (red) infecting vascular endothelial cells ([[Immunohistochemistry|Immunohistochemical stain)]]
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 vascular endothelial cells that line both small- and medium-sized blood vessels in the host's body. There is an extensive immune response to this pathogen that triggers different pathways in the macrovascular and microvascular systems. It does so by depleting R. rickettsii of ATP as nitric oxide targets cytochrome bo oxidase and cytochrome bd oxidase complexes which are necessary for ATP-synthase. The impact of nitric oxide on the metabolism however is significant enough to limit the pathogens ability to attach to host cells. As translation is also majorly ATP-dependent, the introduction of nitric oxide can greatly reduce the process of translation and therefore protein synthesis, making R. rickettsii incapable of subverting the host cell.
Genome and phenotypes
R. rickettsii is an obligate intracellular alpha proteobacterium that belongs to the Rickettsiaceae family. It has a genome that consists of about 1.27 Mbp with ~1,350 predicted genes, It is maintained in its tick host by transovarial transmission. A key feature allowing for differentiation is the rickettsial outer membrane protein, rOmpA and rOmpB ]]The most common hosts for R. rickettsii are ticks. Ticks are vectors, reservoirs, and amplifiers of these bacteria. Once a tick becomes infected with this pathogen, they are infected for life. The pathogen, however, does not harm the tick itself and only causes symptoms in mammals infected by the tick. Both the American Dog Tick and the Rocky Mountain Wood Tick serve as long-term reservoirs for Rickettsia rickettsii, infecting the posterior diverticula of the midgut, the small intestine, and the ovaries. This process, however, is unlikely to play a major role in the maintenance of R. rickettsii within a population. Rickettsial colonization of the ovaries sees higher success when ticks obtain the pathogen as a larva or nymph. Reduced fecundity is also observed in ticks infected with R. rickettsii. 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.
The duration of tick attachment, bacterial loads in tick saliva, and the transmission efficiency of Rickettsia are important factors underlying transmission from ticks to humans.
Transmission in mammals
Due to its confinement in the midgut and small intestine, Rickettsia rickettsii can be transmitted to mammals, including humans.
Transmission can occur in multiple ways. The most common way of contraction is by the bite of an infected tick. The saliva of ticks contain immunomodulatory agents which effect immune defenses in the host. This allows for R. rickettsii to be transmitted with little to no resistance from the host's immune system.
Clinical manifestations
The U.S. Centers for Disease Control and Prevention states that the diagnosis of Rocky Mountain spotted fever (RMSF) 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. R. rickettsii infections in the continental United States are more likely occur during the warmer months between April and September due to its most common method of transmission being via tick bite. Symptoms can take one or two days to up to two weeks to present themselves within the host. If not treated properly, the illness may become serious, leading to hospitalization and possible fatality.
Signs and symptoms
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.
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.
Severe infections
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. One manifestation of this damage is the development of a petechial rash, which in 60% of cases presents within 6 days of initial symptoms. Petechial rashes are indicative of more severe disease progression. Patients 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. The most common and effective treatment for Rocky mountain spotted fever is the anti-microbial agent doxycycline. This antibiotic acts as a bacteriostatic drug by inhibiting protein synthesis via blockage of the 30S ribosomal subunit.
Prevention
thumb|"This photograph depicts, Field EIS officer, Heather Walker, DVM, MPH (EISO Class of '23), as she was placing a flea and tick collar on a community owned dog, for a Rocky Mountain Spotted Fever campaign in Arizona."-CDC
Prevention of Rocky Mountain Spotted Fever begins with identifying and avoiding vectors that cause exposure including ticks, lice, mites, and fleas. Knowledge of where endemic areas are and taking precautions when inhabiting or traveling may also decrease the likelihood of contracting the disease. There are no vaccines to prevent RMSF. Due to increased antibiotic resistance preemptive antibiotic prophylaxis is strongly discouraged in the United States.
When coming into contact with vectors, specifically ticks, there are additional preventative measures that can be taken. Many ticks are present in dense bush, grass, and wooded areas. Ticks also can travel on animals, so caution should be taken with pets. They are under the arms, within and around the ears, inside the belly button, back of the knees, within and around the hair, in between the legs, and around the waist. Clothing can be placed it in the dryer on high for at least 10 minutes. Clothes can washed before drying with hot water. Showering two hours after leaving the outside environment lowers the risk of obtaining Lyme disease, a disease whose vector is ticks, therefore it may assist in reducing the risk of other tick-borne diseases.
History
The first documented case of Rocky Mountain Spotted Fever (RMSF) presented in the Boise, Idaho in 1896 after being recognized by Major Marshall H. Wood. The first clinical description of Rocky Mountain Spotted Fever was reported in Snake River Valley in 1899 by Edward E. Maxey. At the time, 69% of individuals diagnosed with RMSF died.
Howard Ricketts (1871–1910), an associate professor of pathology at the University of Chicago in 1902, was the first to identify and study R. rickettsii on a microbial level. Treatment recommendations changed in the 1990s to support primary therapeutic use of tetracycline-class drugs, and the current recommended treatment reflects this, as doxycycline is most commonly prescribed. Since then, the fatality rate has dropped to between 5 and 10%.