Borrelia burgdoferi

Background check: -Gram negative bacteria -Genus Borrelia -Class Spirochete -causative agent of Lyme s disease -transmitted via white-foot mice and white-tailed deer -by way of nymphs and ticks Surviving innate and adaptive immune response: -Bite from tick of nymph injects bacterium into bloodstream -factors within saliva of vector coat invading spirochetes -help prevent immune system from seeing them -in lab, shown to lodge inside human fibroblasts, mouse macrophages and human endothelial cells -safe intracellular location advantageous for bacterium -long replication time also helps bacterium to fly under the radar -during growth, shed membranous material (blebs) -coat spirochete,interact specifically with IgM molecules -bind all free circulating B. burgdoferi-specific IgM antibodies -enables organism to escape immune surveillance The Central Nervous System (CNS) is comprised of the brain, spinal cord and associated membranes. The CNS is a complex, integrated information-processing system, which exudes control over all systems of the body. The CNS is extremely resistant to infection due to a combination of protective effects of its bony structures, skull and vertebral column, the meninges and the bloodbrain barrier, being the first and perhaps most important line of defense. The blood-brain barriers primary function is to prevent hydrophilic macromolecules in the blood from entering the extracellular CNS. Endothelial cells that form capillaries and venules in the CNS are connected by impermeable tight junctions which prevent all but a few hydrophobic molecules and hormones from penetrating the brain. In order to penetrate CNS, pathogens must combat host defense mechanisms and penetrate protective barriers of CNS. Infections to the CNS can be very serious and difficult to treat, given that is difficult to develop treatment to penetrate the blood-brain barrier, and most immune cells cannot gain access to CNS to ward off infection. The blood-brain barrier becomes more permeable during inflammation being advantageous in that antibiotics can get across, yet increased permeability can be used as a tool for pathogens to invade. Pathogens mainly invade the CNS via hematogenous spread, arterially or retrogradely (veins), or Peripheral Nervous System into CNS, the route many viruses take. Penetration of CNS: -cork-screw shape flagella within body helps bacteria invade tissues and thick mucous that would inhibit most other bacteria -able to physically tunnel through blood vessel wall -once within CNS, become latent and cause illness months later -new evidence that once in CNS, undergo genetic alteration becoming a new strain of spirochete

Toxoplasma gondii
Background check: -Parasitic protozoa -Phylum Apicomplexa -Genus Toxoplasma -obligate intracellular parasite -causative agent of Toxoplasmosis -within oocyst in intestines of cat -transported via ingestion of uncooked meat or cat feces

Treponema pallidum
Background Check: -Gram negative bacteria -Genus Treponema -Class Spirochete -Causative agent of Syphilis -transmitted by direct contact -usually sexual

Bradyzoites within PV

Surviving the innate and adaptive immune response: -oocytes ingested -can invade any nucleated cell type powered by an active process termed gliding motility -invades cells, forms a parasitophorous vacuole (PV) -PV within host cytosol -membrane derived from host cell -within PV, forms bradyzoites (brady = slow in Greek) -prevents normal fusion with lysosome -form cysts that grow and remain intracellular -opportunity for parasite to thrive and proliferate -while within cell, actively interferes with host cell signaling pathways -inhibits intracellular defense mechanisms, modulate cytokine secretion, and regulate cell death

Penetrating CNS: -able to cross blood-brain barrier -process not well understood -hypothesized that parasite is transported via leukocytes in a sort of Trojan horse technique -exploits dendritic cells, targets them for early infection -suppresses their cytokine effector function and uses them for dissemination within host -assistance into an otherwise restricted area

Comparison of Four Pathogens -All eventually penetrate CNS, meaning all must bypass the sophisticated innate and adaptive immune system -overarching pattern of avoiding immune surveillance by way of hiding within host cells, various mechanisms -T. pallidum and B. burgdoferi have very similar mechanisms -both rapidly invade CNS, both spirochetes can pass through or between endothelial cells -Rabies virus and T. gondii replicate within macrophage -T. gondii, B. burgdoferi and T. pallidum utilize a slow replication time to avoid being tagged as pathogenic by immune response - different pathogen types utilize different mechanisms to penetrate CNS, but all are resilient enough to bypass the immune response

Surviving innate and adaptive immune response: -penetrates dermal micro abrasions or intact mucous membranes via direct contact -multiply at point of entry -avoid contact with phagocytes by binding fibronectin to surface -fibronectin is produced naturally by the body and aids in wound healing -therefore, immune system classifies coated bacterium as self -slow replication rate -doubles 30-33 hours in vivo -utilizes slow metabolism to survive in tissues -lacks endo- and exotoxins -lacks LPS therefore is not red-flagged by immune system -ability to obtain sequestered iron -host s transferrin and lactoferrin proteins bind free iron, making it unavailable to most bacteria -able to sequester iron from host proteins -lacks Electron Transport Chain -made up of enzymes that use iron as cofactor -decrease overall demand for iron-ability to have subpopulations survive immune response due to modified antigen -mutated subpopulation can now proliferate in system SHOWN ON RIGHT

Penetration on CNS: -cork-screw shape flagella within body helps bacteria invade tissues and thick mucous that would inhibit most other bacteria -able to physically tunnel through blood vessel wall

Rabies Virus
Background Check: -Single stranded RNA virus -negative sense -12-kb genome -Family Rhabdoviridae -Genus Lyssavirus -Enveloped -Bullet-shaped virion -Encodes five genes -nucleoprotein -phosphoprotein -matrix protein -glycoprotein (G) -RNA polymerase -causative agent of Rabies -acute encephalitis -transmitted in saliva or aerosolized secretions from infected animal Penetration of CNS: -replicates in cells until enough of a concentration exists in the region of the bite that some viral particles come in contact with sensory or motor nerve cells -virus enters axons where there are not myelinated -move up toward neuron s nucleus by retrograde transport -retrograde transport is a natural function of nerve cells to transport messenger molecules from axon to nucleus, where dynein molecules move along microtubules of axon -capitalize on this mechanism to reach spinal cord -arrives in DRG s and spinal cord, then spreads to the brain -multiplies in grey matter of the brain -propagates via afferent neurons to peripheral tissue including the salivary gland where it is excreted

Surviving innate and adaptive immune response: -Binds to nerve or muscle cells at site of inoculation via nicotinic acetylcholine receptors -can bind here for prolonged period because of G protein -G protein spikes bind to receptors on surface of host cell -virus enters by endocytosis and fusion with membrane of the vesicle -In endosome, low pH induces membrane fusion process -viral genome is then able to reach cytosol (uncoats) -replication of the genome occurs -transcribed by RNA polymerase