Tick-borne diseases: Rickettsiae, Rocky Mountain spotted fever(RMSF, Typhus fever, Lyme disease, Q fever

immune response to Borrelia in an inflamed joint

* joint fluid accumulates in joint spaces after dissemination of the spirochete from the skin to the joint (largely neutrophils, complement components, and inflammatory cytokines) -synovial tissues is infiltrated by mononuclear cells including: macrophages, T cells, B cells, and plasma cells

the transmission of Borrelia to the mammalian host and the dissemination of the spirochete to the joint image

*note outer surface proteins (OspA, OspB, and OspC)

The rickettsiae are small (0.3-0.5 x 0.8-2.0 um), Gram-negative, aerobic, coccobacilli that share a common trait with respect to their growth and survival.

- Rickettsiae are obligate intracellular parasites of eukaryotic cells - Reside in the cytoplasm or nucleus of the cell that they invade - Only reproduce inside of a living cell but can survive out of a cell

Borrelia burgdorferi, like the human pathogen Treponema pallidum, is a spirochete. Unlike Treponema pallidum, the bite of a particular tick is responsible for spreading Lyme Disease. What unusual appearance around the tick bite is present in many cases of Lyme Disease?

- Transient inflammatory skin rash known as erythema migrans, target rash which radiates outward from location of (loxodes) tick bite - Single spot with a red ring around the bite

In a few patients who are treated for Lyme disease, symptoms of persisting infection may continue or recur, making additional antibiotic treatment necessary. These chronic sufferers usually display the following symptoms:

- Varying degrees of permanent damage to joints or the nervous system can develop in patients with late chronic Lyme disease - If untreated, Lyme disease can progress to stage III, or late persistent disease, with chronic arthritis, neuroborreliosis and skin disorders

Borrelia burgdorferi, like the human pathogen Treponema pallidum, is a spirochete. what are spirochetes?

- a group of phylogenetically-distinct bacteria that have a unique mode of motility by means of axial filaments (endoflagella)

host factors of severe or fatal R. rickettsii include

- advanced age - male sex - African american race - chronic alcohol abuse - glucose-g-phosphate dehydrogenase (G6PD) deficiency

1. Endemic Typhus Fever

- aka Murine typhus - caused by Rickettsia typhi - is transmitted by fleas found on mice and rats - found world wide and is endemic to areas of Texas and So Cal

Treatment of RMSF is based on

- based on epidemiologic and clinical clues - Serologic assays *no widely available lab assay to provide rapid confirmation of RMSF

clinical diagnosis of Lyme disease

- based on history of possible exposure to ticks, especially in areas where disease is known to occur - combination of symptoms and signs of infection - serodiagnosis to detect anti-borrelia antibodies (isn't useful until later stages)

characteristics of RMSF rash

- begins with small, flat, pink, non-itchy (macules) - located on wrists, forearms, and ankles - the spots turn pale when applying pressure - spots eventually become raised - the characteristic red, spotted (petechial) rash of RMSP usually appears the 6th or later day **only occurs in only 35-60% of patients ***10-15% may never develop a rash

Describe spirochetes motility and how this affects their environment

- by means of axial filaments (endoflagella) - the spirochetes move in cork-screw fashion, this type of movement may be an adaptation to viscous environments such as aquatic sediments, biofilms, mucosal tissues and the intestinal tracts of animals - for pathogens, this allows the spirochetes to hide their flagella, which are normally antigenic, from the host immune defenses.

Lyme disease

- caused by Borrelia burgdorferi - has an outer membrane like most spirochetes, that contains an LPS-like substance, an inner membrane, and a periplasmic space which contains layers off PG (therefore is gram-negative though it doesn't stain as positive or negative)

3. Scrub Typhus

- caused by Orientia (Rickettsia) tsutsugamushi - separate from other rickettsiae though closely related - transmitted by bite of trombiculid mites (chiggers) which are the vectors and host - occurs throughout Asia and Australia

2. Epidemic Typhus Fever

- caused by Rickettsia prowazekii - transmitted by the human body louse - humans are the only reservoir - as the louse feeds it defecates, the bite causes an itch and as you scratch the rickettsiae, the louse's feces are inoculated into the bite - infects human vascular endothelial cells producing widespread vasculitis - occurs in winter

this is a type of serologic assay used to diagnose RMSF

The Mab based immunofluorescence assay (IFA) is generally considered the reference standard in RMSF serology and is the test currently used by CDC and most state public health laboratories.

dissemination of Coxiella burnetii is a result of?

circulation of organisms free in the plasma, on the surface of cells, and carried by circulating macrophages

what is the primary reservoir for human infection of Coxiella burnetii?

livestock

incubation period

period between pathogen's access to the body through portal of entry and the display of signs and symptoms (consistent in some diseases but variable in others)

2-4 weeks of antibiotics is effective therapy for localized and early-disseminated stages of Lyme disease. some patients require longer treatment and can develop chronic symptoms that are unresponsive to antibiotics, as a result of?

post-infectious autoimmune sequelae, not treating the disease earlier

Phase II of Coxiella burnetii

results from serial passage of Phase II of Coxiella burnetii in eggs which results in the bacterium conversion to phase II has a rough LPS and is much less virulent than phase I phase is sensitive to complement and is a poor immunogen

target rash which radiates outward from the location of (loxodes) tick bite are known as?

transient inflammatory skin rash aka erythema migrans

diagnosis of Lyme disease when seroligic test is indicated

- difficult because its signs and symptoms mimic those of many other diseases - testing first an enzyme-linked immunosorbent assay (ELISA) or an indirect fluorescent antibody (IFA) test - followed by a more specific Western immunoblot (WB) test to corroborate equivocal or positive results obtained with the first test *none are useful for diagnosing early stages because primary serum immune response is just beginning

Signs and symptoms of RMSF

- difficult to diagnose in its early stages - patients see doctor after incubation period (5-days after tick bite) - its early clinical presentation is nonspecific and resembles other infections - initial symptoms include rash, abdominal pain, joint pain, and diarrhea

what is Coxiella burnetii classified as?

- genus Coxiella (only species) - isn't closely related to any other bacterial species when comparing 16s RNA

Typhus Fever

- has 2 varieties (endemic, epidemic) and Scrub - rodent control is primary in breaking disease cycle

what characteristics of Coxiella burnetii allow for the development of acute infection following indirect exposure?

- it being spore-like - it's primary mode of transmission is inhalation of infected aerosols

Rocky Mountain Spotted Fever (RMSF)

- most common in southeastern part of US (been found on every continent except Antartica) - most severe tick borne rickettsial disease - Rickettsia rickettsii is the causative agent - transferred by a tick feeding on a human or other mammalian host - bacterium infects human vascular endothelial cells, producing inflammatory response

actue Q fever

- no characteristic illness for acute Q fever - manifestations may vary considerably between locations where the disease is acquired - the symptomatic, onset of Q fever can be abrupt - fever, chills, and heartache are most common signs and symptoms

long-term health problems following acute RMSF infection include

- partial paralysis of the lower extremities - gangrene requiring amputation of fingers, toes, or arms or legs - hearing loss - loss of bowel or bladder control - movement disorders - language disorders.

in what situation would Doxycycline not be used to treat infections caused by Rickettsia?

- pregnancy - tetracycline hypersensitivity

Properties of Rickettsiae diseases

- rod shaped bacteria - diseases caused by these organisms are acquired through the bites of anthropods - they are obligate intracellular parasites - require eukaryotic host cells

Lyme disease has acute and persistent phases, which are subdivided into 3 separate stages, what are they?

- stage I aka early-localized Lyme disease - stage II aka early-disseminated Lyme disease - stage III aka late-persistent disease

there are know spore like forms of Coxiella burnetii, which means

- they are extremely resistant to heat, pressure, desiccation, and many standard antiseptic compounds - allows C burnetii to persist in the environment for long periods (weeks or months) under harsh conditions.

chronic Q fever

- usually manifested by infective endocarditis (most severe complication of Q fever) - also hepatitis, infected vascular prostheses and aneurysms, osteomyelitis, pulmonary infection, cutaneous infection, and an asymptomatic form - immunodeficiency observed in 20% of patients (is it possible that chronic Q fever is result of reactivation of latent infection?)

obligate intracellular parasites

- viruses that are subcellular (simpler than a cell) - therefore, can replicate (there purpose in life) only when inside the cell - they don't have a life outside the cell - takes over cells and make turn them into virus producing machines

Q fever

- zoonotic disease - caused by Coxiella burnetii (which can't grow/replicate outside host cell) - primary mode of transmission is inhalation of infected aerosols

It is now well established that a majority of sequelae associated with human rickettsioses are the outcome of the pathogen's affinity for what cell type?

1. Affinity for endothelium lining the blood vessels, the consequences of which are vascular inflammation, insult to vascular integrity and compromised vascular permeability, collectively termed 'Rickettsial vasculitis' 2. They infect endothelial cells lining the blood vessels 3. Wire brush like effect causes blood to leak out

Types of ticks (3 types)

1. Blacklegged tick 2. Lone star tick 3. Dog tick

alphaproteobacteria are rarely pathogens of humans but the few that are pathogenic are... (4 of them)

1. Brucella 2. Bartonella 3. Rickettsia 4. Erlichia

These 3 are considered "oddball" groups of bacteria, each possess distinctive properties that distinguish them from typical bacteria and each other.

1. Mycoplasmas 2. Chladmydiae 3. Rickettsiae

life cycle of ticks (7 steps)

1. adult female drop off host to lay eggs 2. eggs hatch into six-legged larvae 3. larvae attach to and feed on first host and may acquire R. rickettsii 4. larvae molt into nymphs after leaving first host (can attach to a human after this step) 5. nymphs attach to and feed on second host and may acquire R. rickettsii 6. nymphs molt into adults after leaving second host (can attach to human after this step) 7. adults (both sexes) attach to the third host for feeding and mating *cycle continues

what is the classic triad of findings for RMSF

1. fever (not often present or is very subtle) 2. rash (appears in 2-5 days after onset of fever) 3. history of tick bite * this combination isn't identifies when patient initially comes in *also younger patients usually develop rash earlier than older patients

Lyme disease life cycle

1. large acorn crops attract tick-infested deer and mice infected with Borrelia burgdorferi to oak forests 2. ticks lay eggs the following spring 3. infected larvae molt into nymphs 5. infected nymphs feed on humans from spring through summer, transmitting Borrelia burgdorferi to people

what 3 major groups are rickettsiae subdivided into?

1. spotted fever 2. typhus 3. scrub typhus

Phase variation has been described with Coxiella burnetii, how many are there?

2 phases

An impressive variety of pathophysiological situations affecting ECs of the vasculature leads to the expression of genes dependent on nuclear factor (NF)-κBfamily of transcription factors.

A majority of early response genes transcriptionally up-regulated in response to R. rickettsii and R. conorii infection in vitro contain NF-κ B binding sites in their promoter regions, indicating that infection-induced alterations in the pattern of gene expression may be governed, at least in part, by activation of NF-κ B. NF-κ B is a dimeric transcription factor composed of homo- and heterodimers of the Rel family of proteins, of which there are five members in mammalian cells; Rel A or p65, c-Rel, Rel B, NF-κ B1 or p50, and NF-κ B2 orp52.

Ehrlichiosis, Rocky Mountain Spotted Fever, and many rickettsial infections can be treated with which common and inexpensive antibiotic?

Doxycycline for more pathogenic rickettsioses

what is usually found in patient's liver and bone marrow with Q fever?

Fibrin ring or "doughnut" granulomas (small, non-necrotizing granulomas) with a very distinctive appearance that are usually found in the liver and bone marrow in patients

how does ROS also serve second messenger functions in the vasculature?

The injury to EC following infection with R. rickettsii culminates in widespread dilatation of intracellular membranes, most conspicuously of rough endoplasmic reticulum, loss of osmoregulatory control and cell lysis at 5 or 6 days postinfection

treatment of Lymph disease

The present drug of choice is doxycycline, a semisynthetic derivative of tetracycline. Even patients who are treated in later stages of the disease respond well to antibiotics.

what can develop in patients with late chronic Lyme disease

Varying degrees of permanent damage to joints or the nervous system

a majority of sequelae associated with human rickettsioses are the outcome of the pathogens...

affinity for endothelium lining the blood vessels, the consequences of which are (3): 1. vascular inflammation 2. insult to vascular integrity 3. compromised vascular permeability, collectively termed 'Rickettsial vasculitis'.

stage II

aka early-disseminated Lyme disease - neither EM or influenza-like symptoms are present in initially in patients who develop stage II - symptoms typically involve the organs that spirochetes have disseminated (heart, joints, or nervous system, and include arthritis, carditis, and neuropathies)

stage I

aka early-localized Lyme disease - manifestations include a transient inflammatory skin rash known as erythema migrans (EM) where spirochetes are localized in the skin - manifestations can also include a mild influenza like illness with nonspecific symptoms

stage III

aka late-persistent disease - results from not treating Lyme disease - chronic arthritis or neuroborreliosis and skin disorders

Phase I of Coxiella burnetii

associated with natural infection and a smooth lipopolysaccharide (LPS) this phase is resistant to complement and is a potent immunogen

ECs are crucial components of vasculature (what the virus targets) and exhibit a # of unique properties and serve to maintain vascular homeostasis. They produce and react to a wide variety of mediators including

cytokines, growth factors, adhesion molecules, vasoactive substances and chemokine with effects on many different cell types

Coxiella burnetii contains several plasmids and the plasmid types are associated with

different manifestations of the disease

ECs are key immunoreactive cells involved in

host defense and inflammation

why is conversion from phase I to II irreversible?

it is the result of a mutation caused by chromosomal deletion

R. rickettsii infects

the cells lining bloods vessels throughout the body *severe manifestations may involve respiratory, central nervous, gastrointestinal, or renal system

when ticks attach to a human is considered what part of the life cycle?

the dead end of transmission

the major target of pathogenic Rickettsiae?

the endothelium lining of vital organs in humans *a majority of sequelae reflect infection-induced damage to the vascular system

environment of Coxiella burnetii?

the phagolysosome of eukaryotic cells which has a strongly acidic milieu (normal pH is 4.5) and numerous digestive enzymes. *While inhabiting the phagolysosome, C. burnetii usually lives in relatively peaceful coexistence with the host, causing little direct damage to the cell, initially

what is the basis of rickettsiae and their obligate relationship with eukaryotic cells?

their possession of "leaky membranes" that require the osmolarity and nutritional environment supplied by an intracellular habitat

all cells generate superoxide radical (O2-) and hydrogen peroxide (H2O2), ROS is implicated in a variety of vascular diseases. Normal function of ROS?

to contribute to distinct cellular stresses: heat shock, UV radiation, etc.

how do rickettsiae virus divide?

via binary fission and they metabolize host derived glutamate via aerobicc respiration and the citric acid cycle (TCA)

the majority of noticeable pathologic features associated with RMSF are attributed to

widespread infection of endothelium resulting in: 1. damage to blood vessels 2. altered vascular permeability 3. vascular inflammation/dysfunction collectively termed "Rickettsial vasculitis."

Is RSMF highly resistant to most antibiotics?

yes, fatal cases of RMSF are of patients who have received substantial courses of antibacterial treatment