Vector-Borne Diseases PDF

11/20/24 Cardiovascular system Cardiovascular system circulates blood and lymphatic system carries lymph fluids Supposed to be sterile! (free of any microorganisms!) Infections can be serious, since infectious agents can become systemic, or carried throughout body...

11/20/24 Cardiovascular system Cardiovascular system circulates blood and lymphatic system carries lymph fluids Supposed to be sterile! (free of any microorganisms!) Infections can be serious, since infectious agents can become systemic, or carried throughout body Worst cases – we’ve mentioned before: Cytokine storm—an excessive release of pro-inflammatory cytokines Sepsis—life-threatening tissue damage or organ dysfunction Even if something gets there – blood and lymph are the home of our best immune defenses 3 Also Key Organs Lymph nodes Concentration of immune cells testing lymph for any invaders Spleen Cleans blood of debris (lots of macrophages!) Also acts as a “lymph node for blood” Liver Detoxify blood Also acts as lymph node for blood. 4 2  11/20/24 How get to blood system? We’ve seen a variety of breaches of the mucosal membranes Think TB, UTI, STI Also wound or tissue destruction compromising skin Think Tetanus and other Clostridia Even referred to medical device transmission (e.g., shared needles) Most of those infections are accidental Often dead ends for the infective agent Or at least secondary to its normal cycle of growth and transmission 5 But there is another class of microorganisms Require systemic spread in blood and/or lymph to complete their cycle of infection. Must have regular access to blood or lymph Must have a plan for getting out of the blood or lymph and to the next host. Focus of today’s class – bacteria, viral, parasitic Very successful infective agents, past and present. 6 3  11/20/24 Special group – team up with blood sucking arthropod Injected into blood or lymph And, if high enough presence in the infection – have a built in way to get back to the outside and ready to infect the next host. Some are Zoonosis – infection carried in animals, with transmission to humans by arthropod bite. Others have learned to survive long enough (years?) in the host to ensure transmission from person to person! Generally, they have a very close and specific relationship with both the arthropod “vector” and the human “host” 7 To Quote Jonathan Swift….. Big Fleas have little Fleas upon their backs to bite them. And little Fleas have lesser Fleas and so, ad infinitum! Fleas are ectoparasites, living on animals, regularly sucking blood. Different fleas prefer different animals: cat fleas, dog fleas, etc. 8 4  11/20/24 We are interested in the Rat Flea Normal host – rodents. Add in a bacterial agent: Yersinia pestis Enterobacteriaceae, facultative anaerobe – related to the whole host of gram negative rods we have in our intestine. Non-motile – actually likes temperature a little lower than human body temp. Infects Fleas! Forms biofilms in digestive tract of infected fleas, blocks tract Fleas starve, increasing likelihood of feeding more (or trying to!) Causes bacteria to be regurgitated (vomited) into bite wound Can transmit via feces when host scratches flea bite Fine when it is only Rodents, but…. 9 Combine People & Rats (& different Rats) & War Black Death killed about 25% of Europe’s population between 1346 and 1350 Spread through rat population, but when rats die, fleas take whatever meal than can get. Body lice may have exacerbated response First recorded case of biological warfare – siege of Kaffa (Crimea). Exeption to my statement about surviving in host 10 5  11/20/24 Pathogenesis Proteases destroy complement, break up fibrin clots Where have we heard that before? Multiplies within macrophages Sequesters iron (needed for growth) Injects cells with toxins (proteins) Disrupts cytoskeleton, preventing phagosome development Blocking cytokine production Necrosis in lymph nodes leads to septicemia (and system wide shock – remember LPS) 11 Progress of disease Regurgitate and scratch – infects bite wound. Spreads through lymph to draining lymph node 2-3 days later, major infection/inflammation of lymph node Nodes enlarged and tender à Buboes. Hence Bubonic Plague Necrosis of nodes allow entry to blood system Septicemic plague >50% of untreated cases Systemic infection, high fever, Diffuse bleeding into skin (and clotting – “black” part of black death!) 10% have high levels of infection in lungs à Pneumonic Plague! Spread as aerosol. No longer need fleas… 12 6  11/20/24 Treatment Antibiotics as quickly as possible! Better is prevention – rodent control. Insecticide on fleas. No “good” vaccine – but trying. 13 Endemic Africa, Asia, South America But also western United States In ground squirrel population Please don’t play with the squirrels! 14 7  11/20/24 If you thought Fleas were fun – try ticks Borrelia burgdorferi Gram negative, microaerophilic spirochete Transmission by tick (Ixoides) Tick (or larvae or nymph – any feeding stage) infected by host animal. Infected ticks will carry infection for life. Humans are incidental host. Transmission requires long feeding times. But often do not notice early stage ticks feeding… 15 Pathogenesis and disease Infection progresses through skin from bite site Inflammation (from LPS) as they move outward – bull’s eye rash (Erythema migrans) Local lymph nodes can swell “Flu like symptoms” Worst is yet to come. 16 8  11/20/24 Disseminated Disease Early – 2-10 weeks later Dizzy spells, fainting, paralysis of face Headache, stiff neck, difficulty concentrating Nervous system involvement, including cardiac muscles. Late persistent – 6 months later Joint pain, joint arthritis – excessive inflammatory response in joints Can persist for years. Most common vector borne disease in United States Treatable if you catch at early stages But often flies under the radar. 17 Move to Mosquitoes Mosquitoes largely feed on nectar (sugar) But when females are developing eggs, need protein. Evolved the nectar sipping straw (proboscis) into blood sucking syringe. Males are still nectar feeders. Females are the vampires! Are many different species of mosquitoes Different preferences for blood source Different ecologies for their life cycle Have co-evolved with particular infective agents When talking infections – have to include which genera of mosquitoes can or cannot transmit! 18 9  11/20/24 Dengue is the most common vector-borne viral disease in the world. Enveloped, single stranded RNA virus Often called an “arbovirus”, because transmitted by arthropids Transmitted by Aedes mosquitoes, with Aedes aegypti and A. albopictus Extremely common in urban environments. Migrated world wide – for instance in recycled tires that happen to catch a little rainwater! Preferentially feeds on humans Can reproduce in a bottlecap of water…. If you are sitting outside in El Paso in summer, they are likely the small ones nipping at your exposed ankles! 19 Dengue Disease Progression When Mosquito feeds, first injects a small amount of fluid from its salivary glands (blocks clotting) (also causes the itch of a bite!) Mosquito infected by feeding on infected person. Infected mosquito can then transmit virus via this small amount of fluid. Virus infects local macrophages and dendritic cells(!) Infected Dendritic cells take antigens to lymph nodes, thinking they are starting the defense. Instead, they are spreading the virus through the body – recruiting (and infecting) more macrophages and lymphocytes. Spread to bloodstream and systemic viral infection. Eventually resolves, with long standing immunity to the original strain of Dengue…. 20 10  11/20/24 But if an immune person is infected again, by a different strain…. Antibodies can bind to the new virus, but NOT INACTIVATE! Provides an extra way to infect macrophages (through their antibody binding sites!) Accelerates the time frame of the infection. Multiplies the effect of the disease. Can lead to “bone break fever” Cytokine storm Severe pain in muscles and joints (like bones breaking) Experimental vaccines – but worry might make things worse… Only recommended for people who have already been infected once… Rest of us should try not to get bitten by mosquitoes! 21 Not in El Paso Yet. We have Aedes and we have people…. 22 11  11/20/24 Historical Note: Yellow Fever Another arbovirus – enveloped, ssRNA arbovirus (same genetic group as Dengue) Also transmitted by Aedes. But transmitted through the blood to the Liver and infects liver cells Decreased liver function – jaundice (“yellow”) Decreases clotting capability – many small hemorages in skin Triggers Cytokine storm. High fatality rate. Also carried in monkeys as animal reservoir! Was once extremely common (endemic) in southern and Southeastern United States. 23 Historical Yellow Fever (cont) Was a major impediment to building the Panama Canal – Workforce dying from yellow fever and malaria. Walter Reed – army physician (and John Moran – a soldier who volunteered to be bitten by a mosquito….) showed transmission by mosquito. Also was a major factor in facilitating slavery in the US. “other” source of cheap labor – indentured servants, couldn’t survive working on plantations – would die of yellow fever (and malaria). But slaves from Africa didn’t come down with those diseases They had been exposed in Africa and still had immune response! 24 12  11/20/24 Vaccine Active vaccine An attenuated strain of yellow fever (17D) Provides lifelong immunity 25 Malaria is a disease recognized by everyone… Patient is freezing cold, shivering, piling on blankets – but hot to the touch (Ague) An hour later, patient is burning up with a high fever (and throwing off blankets). Depending on the species of malaria (humans have four), the fever can last for 4 to 8 hours. Then patient breaks out in sweat as the body fights to get the temperature down to normal. Usually exhausted by the stress. Finally, patient wakes up and feels almost normal. Until the whole cycle repeats! And repeats Every 48 to 72 hours. Again, and again. 26 13  11/20/24 Infectious agent – Plasmodium sp. Ancient parasite. Different species infect different animals – evolving side by side. Birds, lizards, amphibians, mice, rats, pigs, primates, humans Each malaria only infects its target species. Each species also has a particular mosquito Bird malaria uses our old friend Aedes Human malarias all REQUIRE Anopheles mosquitoes Four varieties – we will look at the two most common Plasmodium vivax Plasmodium falciparum 27 People think it is a tropical disease, but… Can occur anywhere an appropriate vector mosquito is found Includes Korean peninsula and Siberia! Special strain that hides in the body for 9 months before causing disease! Also used to be endemic in US and Europe Eliminated by controlling vector long enough to wipe out disease Every year a few cases, aggressively tracked down. 28 14  11/20/24 Complicated life cycle -- Multi stage infection in both Mosquito and Humans In human Mosquito injects a long, slender sporozoite into the blood stream The sporozoite quickly travels through the blood to the LIVER Disappears after about 30 min – no time for immune response. In liver cells, sporozoite transforms to a trophozoite that divides into thousands of merozoites contained in a large structure – a schizont. Went from one invective agent to up to 100,000… Still hidden from immune system Infected liver cell ruptures, releasing merozoites into bloodstream The merozoites quickly bind to and invade red blood cells Disappear from circulation within 10 min – no time for immune response. 29 Red Blood cells Small. From a parasite point of view-- very limited diet – essentially only hemoglobin Also contains potentially poisonous iron complexes With limited resources, each merozoite converts to a ring stage to a trophozoite and then a schizont, but with only a limited number of merozoites (same name and similar structure to liver stages) And then the fun starts. 30 15  11/20/24 All infected red blood cells rupture at the same time, releasing their merozoites. Remember those periodic fevers? Lysed red cells and parasite debris suddenly appear in the blood. Body detects a massive septicemia – pulls out all the stops with systemic inflammation, going after the debris While everyone is racing to deal with the emergency, the merozoites invade new red blood cells (again, about 10 min) and disappear. Hours later, the body (and especially the spleen and liver) have cleaned up most of the mess and are declaring victory against the invaders! And then all infected red bloods cells rupture at the same time… 31 Lots of antibodies are made and macrophages activated But they all target the debris, not the infective agent Can see enlarged spleen and liver – with no real benefit! 32 32 16  11/20/24 A special feature of P. vivax While passing through the liver, some parasites decide to wait before growing – essentially hibernating. Can result in “Relapsing” malaria Multiple infections even without mosquito bites Also the mechanism for surviving winter. 33 Some Special features of P. falciparum While growing in red blood cells, make sticky knobs that adhere to capillary walls Limits the number of times they pass through the spleen Detach just before time to rupture! All you see in blood are ring stages Unfortunately, they can cause trouble , depending where they stick. 34 17  11/20/24 P. Falciparum Binding to capillaries Placenta is a favorite target, with localized inflammation and damage to fetus. Some studies showing that pregnant women are especially targeted by mosquitoes, as well! Other target is brain capillaries – Cerebral malaria High fatality rates. 35 What about the mosquito? Every now and then, an infected red blood cell takes a different path and develops into male and female gametes. Still hidden from immune system (and each other) inside individual red blood cells. These don’t rupture, but stay in circulation, waiting to taken up in a blood meal by an Anopheles mosquito In the mosquito Tmperature change signals for gametes to come out of red blood cells and have an orgy Fertilized zygote developes into a large structure on mosquito stomach wall Releases sporozoites that move to the salivary glands, ready to infect the next person bitten! 36 18  11/20/24 Food for thought Infected human must be bit by an adult anopheles mosquito Mosquito must take up parasite and survive another two weeks After two weeks, must find and bite a susceptible human host Amazing that it works so well! 37 If Time: How Bad is Malaria? Anybody can see Disease numbers and History I could try and impress you with stories. But evolution has given us a score card. Several different human mutations to try and control malaria. But one stands out à Sickle Cell 38 19  11/20/24 Sickle Cell Single Amino acid mutation ( à V) in one of the subunits of hemoglobin (Hb) Hb “slightly” more hydrophobic (but in cell, very concentrated colloid!) If low oxygen levels in red blood cell, Hb crystallizes, distorts rbc, destroyed by spleen Any child who is homozygous for sickle Hb will die unless massive medical intervention – not available where this mutation was selected for. However, if a child is Heterozygous (one gene each, normal and sickle) the readily survive into adulthood AND have some level of protection (milder disease) to malaria. 39 Cross of two “Trait” parents A S A A/A A/S Protected S S/A S/S Protected dies Malaria is so bad that it is worth killing A fourth of your children for a little extra Protection for half of them… 40 20