pbhlth 162a final!!!!!!

what determines if infectious disease eradication is possible?

pathogen characteristics

• no/limited non-human reservoirs

• easily identifiable/clear diagnostics

• emerging resistance to intervention

• minimal susceptible population needed for pathogen to survive

• mode of transmission

• vector control

intervention effectiveness

• efficient and practical interventions: vaccines

• reduce and susceptible population significantly

technical and operational factors

• practical diagnostics

• effective surveillance systems

socionomic and poltical factors:

• strong societal and political commitment

• funding/cost effectiveness

if eradication is not possible, what should we aim for?

disease elimination in a specific area/population

disease control: reduce incidence, prevalence, morbidity, or mortality

targeted interventions: areas of highest disease burden and tailored approaches based on local conditions

addressing social and economic factors/strengthening health systems

where do emerging infectious diseases come from

viruses: mostly zoonotic infections

bacteria: mostly emergence of antibiotic resistance

emerging infectious diseases: viral pathogens

covid 19

crimean congo hemorrhagic fever

ebola virus and marburg disease

lassa fever

MERS-CoV

Zika

Rift valley fever

what should we do for emerging diseases?

building vaccine, clinical testing, and pre-clinical capacity

enhance global surveillance to detect human or animal outbreaks

establish communication structures

improved building design and operation to limit disease transmission

technology/workforce development/collaboration

vaccine development

antibiotic development

pathogen surveillance

epidemic modeling

education

pathogen surveillance

environmental and wastewater sequencing can provide real time information

easier and more accurate than relying on mass testing/self-reporting

endemic diseases

tuberculosis

respiratory infections

diarreal diseases

malaria

helminths (worms)

emerging/reemerging diseases

aids

mutidrug resistant TB

dengue

hanta (HPS)

lyme disease

ebola

leptospirosis

cholera in the americas

covid 19

key factors in endemic diseases

poverty

poor sanitation/hygiene

malnutrition

overcrowding

key factors in emerging diseases

international trade and travel

economic development and land use

• deforestation

• new roads, mines, plantations

• contact with wild animals

ecological and climate change

behavioural and demographic cange

technology and industry

microbial adaptation (antibiotic resistance)

breakdown of public health

susceptibility: lack of immunity

the convergence model

factors influencing the outcome of microbial infections

center of the box represents the convergence of factors leading to the emergence of infectious disease

black center represents unknown factors: “black box”

model indicates that all factors are interlocking

zoonotic infection

a human infectious disease originating from an animal reservoir and not requring the human as part of its life cycle

• infectious agent/disease that can successfully circulate among animals without the host

• diseases where human is required for life cycle are NOT zoonotic

  • helminths

  • other infections with animal intermediate

current zoonotic diseases may be due to…

more recent exposure of humans to microorganism

slower evolution of host-parasite relationship

Diseases that were zoonootic, but now exclusively human

small pox virus evolved from camelpox virus

measles virus from reinderpest virus of cattle

mycobacterium tuberculosis from M.bovis

HIV from SIV (simian immunodeficiency virus)

ebola virus

linear non-segmented ss - RNA genome

filovrius: appears as filamentous particles in the shape of a hook

first discovered near ebola river in Congo

ebola virus: natural reservoir

fruit bats in the Pteropodidae family are considered the natural host

ebola virus: transmission TO humans

transmitted to people from wild animals

close contact with blood, secretions, organs, or other bodily fluids of infected animals

in africa, infection has been documented through the handling of infected champanzees, gorillas, fruit bats, monkeys, forest antelope, and porcupines found ill/dead in rainforest

ebola virus: transmission AMONG humans

direct contact with blood or bodily fluids of an infected symptomatic person

exposure to objects (needles) that have been contaminated with infected secretions

viruses often spread through families and friends that come in close contact with infectious secretions when caring for ill persons

ebola virus: transmission in health care settings

hospital staff not wearing appropriate protective equipment: masks, gowns, gloves

lack of proper cleaning and disposal of instruments (needles, syringes)

• inadequate sterilization of instruments reused

symptoms of ebola

treatment of ebola

balance pateints fluids and electrolytes

maintaining oxygen status and blood pressure

treating for any complicating infections

monoclonal antibodies

ebola prevention

express ebola glycoprotein on surface of vesicular stomatitis virus (VSV), a benign virus that causes asymptomatic or mild flu-like symptoms in humans

rabies

ss - RNA, enveloped virus

rhabdovirus: rod/bullet shaped

most deadly infectious disease known

does not follow iceberg pattern

reservoirs of rabies

wild and domestic animals

• rabid cat

• fox

• bat

• mongoose

• racoon

• skunk

transmission of rabies

virus shed into saliva and transmitted when animal bites the human

enters via animal bite/skin break, replicates locally, migrates to neurones

may also be transmitted via exposure to bat feces

pathogenesis of rabies

virus multiples initially in tissue around bite

travels up nearby peripheral nerves to brain (1-3 months), then destroys cells in the CNS

moves to salivary glands

clinical manifestations of rabies

spinal cord, brain: acute encephalitis

infection to symptoms: 20-60 days

pain at site of wound: bat bites may be painless

neck pain around 2 months later

loss of control of movement

throat muscle paralysis: difficulty swallowing

• drooling

• hydrophobia (fear of water)

behaviour change: extreme agitation

coma

death 3 months after exposure

diagnosis of rabies

usually after death, using autopsy material from animal or human

• negri bodies in the brain

• PCR of brain / other material

samples taken from wound

• fluorescent antibody test

• PCR

treatment of rabies

no established antiviral treatment available

immunological treatment:

• passive immunization injected

• active immunization with inactivated vaccine; 2 injections in the arm, each 1 week apart

  • secondary prevention

  • virtually 100% effective

rabies prevention

animal control

• required vaccinations of dogs

• quarantine of imported animals in countries/areas that are rabies free

• wildlife surveillance and reducing stray, unvaccinated dog and cat population

vaccination of people at risk of exposure

• occupational

  • outdoor work with wildlife exposure

  • laboratory personnel

• travelers to high risk areas

education of the public

toxoplasmosis

Toxoplasma gondii

protozoan parasite

Apicomplexa phylum

reservoir: cats and other feline

definitive host: cat

reservoir of toxoplasmosis

cats and other felines

transmission of toxoplasmosis

cats are definitive host: sexual cycle occurs only in intestine of feline family

transmission occurs from ingestion of material contaminated with cat feces

bird, rodents, ungulates, humans are intermediate hosts

• T.Gondii forms cysts in their tissues

• transmission can occur from eating undercooked beef

toxoplasmosis epidemiology

ubiquitous

• invades all cell types

• worldwide zoonosis

seropositivity increases with age

opportunistic infection associated with AIDS

clinical manifestations of toxoplasmosis

infection in most adults asymptomatic due to control by the immune system

infection severe and possibly fatal in immunocompromised individuals due to encephalitis, neurologic diseases

small children: fever, rash, pneumonia, encephalitis

toxoplasmosis effect on fetus

T.gondii can cross placenta in 40% of fetuses of non-immune mothers

• mismarriage

• 12% of babies die shortly after birth

• <20% are normal after age 4

• damage to central nervous system

  • hydrocephaly

  • blindness

  • mental impairment

  • motor disturbances

diagnosis of toxoplasmosis

direct smear of material from spinal fluid or blood

ELISA serum antibody test

PCR

treatment of toxoplasmosis

sulfonamides, pyrimethamine, sulfadiazine (inhibit folic acid synthesis)

protozoans need folic acid in greater quantity than host cells

prevention of toxoplasmosis

avoid eating raw or undercooked meat

prophylactic antimicrobials for a non-immune pregnant woman who has been exposed

don’t have a cat, or have an indoor-only cat

if there is an indoor-outdoor cat

• use hygienic food preparation practices

  • keep cats off kitchen counters and eating table

  • wash hands between handling cat and preparing food

• be cautious in handling kitty litter

  • pregnant women should not empty kitty litter

effect of toxoplasmosis on mice

mice infected with toxoplasmosis lose their instinctive fear of the smell of cats

parasites effect may be permanent

toxoplasma and behaviour manipulation in animals

animals: greater predation of intermediate host by definitive host

• increased non specific movements, more active

• reduced neophobic behaviour (less fear of new scents, sounds)

• reduced aversion (fatal attraction) to cat urine

• reduced learning behaviours

toxoplasma and behaviour manipulation in humans

humans (chronic infection)

• schizophrenia

• suicide attempts associated with seropositivity to T Gondii

• epilepsy

• Congenital toxoplasmosis may reduce brain function

• loss of psychomotor performance

• men become more jealous, emotionally unstable, suspicious, short tempered, low self esteem

• women and men more anxious

plague

Yersinia pestis

gram - cocobaccilius

reservoirs: praire, rat, chipmunk, squirrel

transmission of plague

requires the flea as a vector

• bacteria multiply in flea gut and block it, causing flea to regurgitate infected material when flea feeds on a new host

• flea is in a starving state so bites frantically

bubonic plague

• Y. pestis multiplies in lymph fluid and lodges in lymph node nearest the site of flea bite

• bubo = enlarged lymph node black from hemorrhage and fever occur within 2-6 days

• disease not communicable among humans at this stage

pneumonic plague

occurs in 5% of plague cases

bacteria enter blood and disseminate to lungs, causing pneumonia

within 1-3 days skin becomes bluish to black from hemorrhage and lack of oxygen (black death)

disease is communicable among humans in this stage through respiratory route

mortality virtually 100% within a few days if early treatment not given

diagnosis of plague

patient sample from a bubo or gram stain (gram - coccobacillus)

direct smear made with laboratory antibody bacteria

rapid dipstick test for field testing of humans measures Y.pestis in human blood reacted with laboratory antibody to Y.pestis

treatment of plague

lancing/drainage of buboes

steptomycin, doxycycline, other antimicrobials

treatment effective if given early enough but diseased may not be recognized early enough

prevention of plague

surveillance for dead rodents in endemic areas

• if surveillance shows positive animals, rodent extermination in residential areas

posting of warning signs

inspection of ships for rats to prevent transport to a new area

rat guards on mooring ropes

education of tourists not to feed squirrels and chipmunks out of their hands

use insect repellant outdoors in endemic areas

prophylatic antimicrobial after probable exposure

vaccination for people in high risk occupation

anthrax

bacillus anthracis

large, gram + bacilli, facultative anaerobe, endospore forming

• endospores only form under aerobic conditions

zoonotic disease

herbivores: sheep, goats, cattle, reindeer - acquired for contaminated soil

carnivores infected from consuming meat

reservoir: animals (contaminated soil)

transmission of anthrax

human: contact with endospores during occupational exposure on farms/industries= wool, hides, meat, bones

wool sorters disease: respiratory anthrax

clinical manifestations of anthrax

cutanous anthrax: skin lesions, center black and necrotic

intestinal anthrax: symptoms mimic food poisoning

• lesions/ulcerations in digestive tract

• can lead to septicemia and death

• outbreak from unpasteurized goats milk cheese

respiratory: most deadly; most concern with bioterrorism

• symptoms similar to flu

• inhaled into lungs, spores germinate in alveoli

• phagocytized by macrophages, replicate

anthrax diagnosis

blood culture

gram stain

culture of external lesions

serological tests

PCR assays

treatment of anthrax

ciprofloxacin (fluoroquinolone)

penicillin

doxycycline

erythromycin

prevention of anthrax

human vaccine: 6 doses over 18 months

reduce exposure to endospocres

dispose of infected animals properly

vaccinate animals

one health triad

encompassing the collaborative goals providing optimal health for people, animals (domestic and wild) and the environment by considering interactions between all 3 systems

definitive host

an organism that harbors the adult, sexually reproducing form of a parasite

intermediate host

an organism that harbors a sexually immature stage of a parasite

biological vector

an arthropod that actively transmits pathogens that complete part of their life cycle within the organism

mechanical vector

vector in which the pathogen does not complete any part of its life cycle during transit

vector-borne disease vectors

ticks, mosquitoes, biting flies, fleas, blood feeding bugs, mites, lice

require a blood meal for their eggs to mature: proteins and nutrients in blood essential for egg production

feed in different ways: - piercing-sucking, tearing-rasping - suggests blood feeding evolved multiple times

molecules used by blood-feeding parasite

• Anticoagulants: These molecules prevent the host's blood from clotting, making it easier for the parasite to feed. Parasites need to stop coagulation to ensure the blood remains liquid for feeding.

• Vasodilators: cause blood vessels to dilate (expand), making it easier for the parasite to access blood. By widening the vessels, they increase blood flow to the feeding area.

• Anesthetics: Parasites release these to numb the host so they don't feel the bite as much. This helps the parasite feed undisturbed, as the host won't notice the bite right away.

• Immunomodulators: help parasites evade the host's immune system, allowing them to feed without triggering an immune response. By modulating the host's immune system, parasites can avoid detection and continue feeding longer.

targets for vector-borne disease

• Human Host Interventions:

  • Anti-parasite/pathogen therapies: target the parasite or pathogen after it has entered the human body to reduce or eliminate the infection.

  • Vaccines: boosting the human immune response to the parasite/pathogen before or after exposure.

• Arthropod Vector

  • Genetically modified vectors incapable of reproduction or pathogen transmission

  • Attractants/repellants and behavioral modifiers: Chemicals or tools that either attract or repel the vectors, making it harder for them to transmit diseases to humans.

  • Novel insecticides:

  • Vector longevity curtailers: Methods to shorten the lifespan of the vector so that they don't live long enough to transmit pathogens effectively.

• Parasite/Pathogen Interventions:

  • Vaccines blocking parasite acquisition or transmission by arthropods: Vaccines that target the parasites within the arthropod vector, Insect immune regulators (smart sprays): substances that regulate or enhance the insect's immune system, potentially stopping the parasite/pathogen from being transmitted to the next stage of the life cycle.

general strategies to interrupt transmission of vector borne disease

vectors

• Kill vector or alter vector competence for microbe

• Inhibit feeding on humansń

Pathogen

• Block transmission

• Inhibit uptake

Humans

• Vaccinate

• Diagnose & treat

Reservoir

• Eliminate reservoir

• Vaccinate or treat reservoir

types of viruses

dengue

zika

west nile

dengue virus

Family: Flaviviridae

Genus: Flavivirus

+ssRNA virus

uncontrolled spread of dengue

Increase in numbers of cases

Geographic dissemination

Co-circulation of multiple serotypes

dengue epidemiology

spread of multiple serotypes

• global trade and travel

• urbanization

clinical manifestations of dengue

dengue fever:

• high fever, headache, retro-orbital pain, fatigue, nausea, vomiting, cutaneous rash

dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)

• increased vascular permeability, hemoconcentration, hypovelmic shock, hemorrhagic manifestations, thrombocytopenia, abdominal pain, cytoskin storn

sequential infection of dengue

while the body builds immunity to one dengue serotype after a primary infection, a secondary infection with a different serotype can lead to a more severe illness due to ADE, increasing the likelihood of complications like Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS).

Antibody dependent enhancement (ADE)

occurs when antibodies from a previous dengue infection worsen a secondary infection by helping the virus infect more cells, leading to more severe disease

integral hypothesis of dengue

it’s not just one factor but the combination of personal characteristics, environmental conditions, and viral properties that determines the risk of dengue infection and its severity.

dengue diagnosis

Clinical

Serology

RT-PCR

dengue prevention

Mosquito control

Wolbachia – common obligate intracellular endosymbiotic bacteria of insects

• disrupt/alter symbiotic relationship to affect vector competence (shorten mosquito lifespan, reduce level of pathogen, etc.)

Vaccine: challenging

• Must include all 4 serotypes

• Only licensed vaccine has safety issuesh

zika virus

ss(+) RNA virus

Belongs to family Flaviviridae; genus Flavivirus

spread by the bite of an infected Aedes species mosquito

can be passed from a pregnant woman to her fetus; Infection during pregnancy can cause certain birth defects

Local mosquito-borne Zika virus transmission in the continental United States

clinical presentations of Zika

onset of symptoms by Day 1 post infection, last until day 5

• most pateints feel better after day 3

maculopapular rash, conjuncivitis, fever, arthralgia, and myalgia

rarely: vomiting, edema, myalgia

guillain-barre syndrome

microcephaly and congenital zika syndrome

viral encephalitis

inflammation of the brain

variety of viruses (togavirus, flavivrus)

• west nile virus (WNV): widespread in USA

mosquito: biological vector

west nile virus

flavivirus

ss + sense

enveloped

spread throughout USA< multiple species of mosquitos, 60+ species of birds, mammals, reptiles, and humans

asymptomatic, west nile fever, encephalities

illness primarily in elderly and very young

life cycle: mosquito-bird-mosquito

viral encephalitis: prevention and control

surveillance

• Blood screening

• Mosquito traps/pool testing for viruses

• Sentinel chicken flock immuno-serological testing

• Dead bird testing for virus (esp. WNV)

• ArboNET

mosquito control

• eliminate standing water, mosquito fish, standing water

• public education

• larvicides

• avoid mosquito bites

lyme disease epidemiology

30,000 cases reported to CDC every year; may be ~300,000 (clinicians, commercial labs)

Most cases in New England and Great Lakes

Seasonality: Late spring and summer in United States

lyme disease transmission

Borrelia burgdorferi

vector:

• ixodes scapularis: new england and midwest

• ixodes pacificus: west coast

need 48-72 hours to disseminate from tick to human

seasonal temporaility

• most transmission in late spring and summer by nymph stage ticks

lyme disease: clinical

• incubation: 3-32 days

• stage 1: 70-80% pateints

  • erythema migrans (EM) rash

  • malaise

  • fatigue

  • fever

  • myaglia

• stage 2: 5% of untreated pateints

  • weeks to months folliwng EM

  • neuritis, carditis, meningitis

• stage 3: 60% of untreated pateints

  • weeks to years following EM

  • arthiritis, joint pain, swelling

lyme disease virulence factor

one of few pathogenic bacteria that can survive without iorn

• enzymes use manganese, avoiding the problem many pathogenic bacteria face in acquiring iron

endoflagella: motility in viscous environment (mucosal tissue)

• hide flagella antigens

lyme disease diagnosis

clinical

challenging in stage 2/3

isolation of B.burgdorferi (from captured tick)

significant change in IgM and IgG antibody

lyme disease treatment and prevention

antibitoics: only early after infection

• EM: doxycycline/amoxicillin

• neurological: IV antibiotics

prevention:

• repellent and barriers

• immediate tick removal

malaria etiology

phylum: apicomplexa

5 species of plasmodium

• P falciparum: worldwide, most serious

• P. vivax: rare in reuatorial africa, common in ammericas

• P. malariae

• P. Ovale. P. knowlesi

vector: anopheles sp mosquito

malaria epidemiology

• majority of cases in africa (95%)

• infants protected form infection by transfer of maternal Abs

• young children at greatest risk of infection

• non immune hosts at highest risk for complications and death: travelers, young children

attempts at malaria control

WHO’s worldwide eradication of malaria program (1957)

• Widespread use of antimalarial drugs (e.g., chloroquine) in humans

• Use of insecticide DDT to control the mosquito vector

Program failed to eradicate or even control malaria

• Rise of parasites resistant to chloroquine, pyrimethamine, etc

• Anopheles resistant to DDT

Now improved control methods; in 2018, Gates Foundationlaunched Malaria Eradication Program

• Insecticide-treated bednets

• ndoor residual spraying

• Artemisinin combination therap

But, problems of resistance to insecticide and drugs

hypnozoites

in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later

malaria clinical manifestation

• High fever and chills (due to blood stage cycle)

• Anemia (ruptured blood cells decrease oxygen transport)

• Splenomegaly (spleen enlarges due to abundance of ruptured RBCs that needs clearing from circulation)

uniquely P. falciparum:

• cerebral malaria: capillaries clog in the brain

• renal failure: capillaries clog in kidney

• pulmonary edema (fluid in lungs)

• severe anemia

• shock: excess antigen in bloodstream

why is p falciparum more virulent

can infect RBCs and erythropoetic (RBC) stem cels, exacerbating anemia

avoid clearance from spleen (survival strategy 1)

• surface antigen in infected RBCs (pfEMP-1) binds adhesion molecules on endothelial cells in capillaries

PfEmp1 on RBC surface can bind platelets and other infected RBCs (rosetting)

by adhering to capillaries and rosetting, infected RBCs can clog blood flow to vital organs

where the capillaries are obstructed leads to particular clinical manifestations

p falciparum antigenic variation

• survival strategy 2

• P. falciparum evades the immune system by changing its surface antigens in a process called antigenic variation, leading to waves of immune responses.

• parasite creates "waves" of antigen variation as each parasite clone switches its surface antigens, continuing this cycle until the parasite runs out of infected RBC surface antigens and matching endothelial cell receptors.

• This strategy allows the parasite to persist in the host for a long time, even as the immune system gradually catches up to each variant.

• Over time, after exposure to many variants, the host develops clinical immunity, allowing them to carry the parasite without experiencing symptoms, although the infection isn’t completely cleared.

treatment of malaria

chloroquine

• resistance very common in P.falciparum infections

• growing resistance in other plasmodium species

mefloquine

• common chemoprophylaxis in travels

• associated with weird dreams

antibiotics (doxycycline): used for chemoprophylaxis

arteminsins

• used as herbal remedy in china for thousands of years

control & prevention of malaria

insecticide-treated bed nets

indoor residual spraying

chemoprophylaxis in travelers

repellents/long sleeved clothing

drain pools of standing water

vaccine: 3 doses + booster (1y)

• low to moderate efficacy

• relatively short-lived

onchocerciasis

etiology: enchocerca volvylus

• filarial nematode

organism

• adult worm

• can live 15 years and release 700 microfiliare a day

vector

• infected black of simulium sp

• blackflies breed near fast-running water

onchocerciasis disease

microfilaria travel to subcutaneous tissue, mature into adults and reside in nodules

microfilaria in circulation travel to skin to be transmitted to biting fly

microfilaria migration causes extreme itching

• lichenification

• skin infections

• sleep

microfilaria migration to eye causes blindess

immunopathogenesis of river blindness

• 4th leaving cause of blindness worldwide

• microfilaria travel to corneal stroma and release wolbachia & wolbachia products when they die or release products

• wolbachia LPS-like protein triggers macrophage and eosinophil chemotaxis to stroma and release cytokines

• inflammation causes keratitis (corneal clouding) and blindess

wolbachia

Endosymbiotic bacteria in both adult worms and microfilaria

Required for embryogenesis

Can use drugs (e.g., doxycycline antibiotic) that target the Wolbachia and kill the adult worm)

onchocerciasis diagnosis

Skin snips for microfilaria
ID adult worms in nodules