Biol 364 Test 2

Flu seasons

-Spike during winter in USA

-during Covid, respiratory deaths greatly increased, but flu infections dropped significantly due to masking and social distancing

H5N1

-Avian influenza spread from Asia to Europe to Americas by migrating birds

-highly deadly

-no human to human transmission

-found in poultry workers

-leads to cullings of poultry

Flu virus components

-10ish RNA strands which provide template for 10 viral proteins

-matrix of proteins surrounds RNA

-lipid bilayer (cell membrane) stolen from host cell

-2 embedded viral proteins: Hemagglutinin (H) and Neuraminidase (N)

H and N

-virus surface proteins

-H fits into host cell receptors and allows virus to enter host cell

-H must have a tight bond which is why only some flu strains jump between species

-Human respiratory and digestive tracks have lots of H receptors

-N cleaves the new virus from the host cell

-H and N proteins define flu strains: H5N1, H3N2

-H and N have the highest mutation rates of viral proteins leading to many different versions of the flu, changing infection rates, and perhaps lowering immune response effectiveness

Virus Reproduction

1. H protein binds to receptor on host cell

2. Virus material dumped into host cell

3. Host cell hijacked to copy RNA strands and create viral proteins

4. RNA and proteins packaged into host cell membrane

5. N cleaves new virus from host cell

Avian Influenza

-Natural cycle is between shorebirds and waterfowl

-Can spread to poultry and swine and from there to humans

-no human to human transmission

-prevent by limiting contact with livestock, wild animals, dead animals, use PPE, food safety, wash hands, less wet markets

Flu types

A: humans, birds, and swine (targeted by flu vaccine, main cases)

B: human to human (one strain usually in vaccine, not as important as A) (one of two types lost since covid)

C: pigs and humans (not very important)

D: Cattle

Flu mutations

-H and N have highest mutation rates

-mutations can influence infection and immune response

-antigenic drift or antigenic shift

Antigenic drift

1. Slow, progressive accumulation of mutations which can potentially lead to a new strain

2. In an immune host, antibody blocks H protein from binding to host cell and prevents infection

3. If an H protein mutates so that the antibody can’t block it, infection will occur

4. Only a few mutations are successful

Antigenic shift

1. large, fast changes caused by recombination of 2 strains during simultaneous infection

2. could cause next pandemic

3. During simultaneous infection of the same host cell in a bird/pig/human, genes from two strains may become mixed

4. New mix could include high transmission and high mortality genes creating a highly infectious and severe new strain

5. doesn’t seem to happen often

Flu vaccine production

1. WHO monitors flu strains year round (looking at Southern Hemisphere can provide clues about NA)

2. in March, FDA chooses 3-4 strains to include and send them to manufacturers

3. in summer, manufacturers grow viruses in eggs

4. through early fall, viruses are extracted, killed, combined and tested

5. starting August, vaccines are packed and shipped out

6. October on, people are vaccinated, immunity takes 2 weeks to develop

New flu vaccines?

-cell based cultures

-recombinant technologies

-universal flu vaccine?

-combined mRNA vaccine for flu and Covid?

Tamiflu/Antiviral flu drugs

-must be used early in infection to be effective

-they short circuit the virus lifecycle by preventing it from leaving cells

-Tamiflu inhibits N, so that the virus’ connection to the host cell isn’t severed and no new virus is released

-they work against any strain so they can be stockpiled, however, over use could lead to drug resistance

Disease ecology

The study of how species interactions and abiotic components of the environment affect patterns and processes of infectious disease, including mechanisms and scale of pathogen impacts on hosts, populations, communities, and ecosystem function

Epidemiology

The study of the distribution and determinants of disease in human populations

Ecoepidemiology

the study of the ecological effects that are prevalent in certain localities or population groups, communities, and ecosystems and their potential causes

Zoonotic diseases

Infectious disease transmitted to humans by nonhuman, vertebrate animals (not insects which are vector borne)

4 Coronavirus types

-Alpha and beta infect humans. Also rats, bats, and cows, camels

-Delta and gamma infect birds

2003 Sars CoV outbreak

-SARS = Severe Acute Respiratory Syndrome

-only infectious after symptoms occur, so people showing symptoms were quickly isolated which stopped outbreak

-highly deadly

Covid-19 virus parts

-Spike protein is a protein on the outside of the virus and binds to the receptor on the host cell

-ACE2 receptor is on host cell and spike protein binds to it

-Furin is on host cell and increases binding between spike protein and receptor is spike protein has a furin cleavage site

-Antibodies will bind to spike proteins and prevent infection, T cells will recognize and destroy infected cells

Ro

How many people are infected by each one new infection

Why Covid is difficult

-it spreads asymptomatically and presymptomatically

-it mutates for higher transmissibility (Ro=3 at beginning, Ro=7 for Delta)

-lots of variants which evade some immune responses either from vaccines or infections of previous variants

-it causes a diversity of symptoms and variety of severity

-it’s both acute and chronic

Why Covid isn’t just the flu

-more transmissable

-number of people infected is higher meaning more hospitalization and death

-covid isn’t as seasonal

-covid has more long term effects

Covid origins

-studies found other bats in Asia with similar virus

-Wuhan wet market was epicenter of outbreak, lots of human and animal interaction in the market

-virus most likely came from a bat, probably from two zoonotic events

-possible accidental infection from Wuhan Institute of Virology which studied coronaviruses

-wild bat viruses lacked furin cleavage site, possibly added by lab?

Early Covid lessons

1. spread based on social interactions: #, length, proximity, showed tragedy of the commons

2. long term situation

3. masks work to protect others and yourself, 80% indoor masking in 2022 could have decreased mortality 2-3x

4. need to base decisions on RAs and epidemiological criteria, when Michigan schools opened before goals were met, cases surged

5. mitigation strategies do work

6. taking action early in a surge is key

7. using a variety of targeted actions is most effective

8. neighboring states are linked/show similar patterns

Disease ecology, one Health, and RAs for Covid

-Disease ecology: includes species interactions and abiotic factors in studying disease distribution and spread

-One health looks at human-animal interfaces, poor health systems, and air travel on a global scale to predict where next zoonotic disease may occur. Suggests importance of international aid to support health services around the globe.

-One health perspective in China has led to legislation to reduce eating wild animals and wet markets to prevent another zoonotic spillover

-RAs: governments and organizations lacked experience making science-based decisions and public health fields weren’t super helpful in a pandemic scenario. Risk assessment, mitigation, communication, and ethics would all be helpful for addressing the pandemic. Chemical risk assessors are also experienced in dealing with invisible threats that have multiplying exposures, multiple causal factors and interactions, uncertainties and controversies, and know how to create mitigation plans based on data.

-RA study showed that COVID infection is lower risk outdoors, wearing a mask, in low occupancy, short term, and silent environments

-Michigan schools didn’t base decisions on the numbers which lead to an increase in infections

Zoonotic disease risk regions

Next zoonotic disease most likely to emerge in one of these regions due to high human-animal interaction, poor health infrastructure, and global air travel: Southeast Asia, Sub-Saharan Africa, Central America

Why respiratory infections are worse in fall/winter

1. more time spent indoors

2. less humidity allows respiratory droplets to persist longer and travel further in the air which increases chance of infection and initial viral load

3. viral particles persist longer in the cold

4. cold, dry air makes innate immune response in respiratory tract less effective

5. less sunlight means less vitamin D which supports the immune system

Early COVID geography

-more cases in cold northern hemisphere early on

-China study showed higher transmissibility (Ro) in colder, dryer areas

Air pollution and Covid

-Air pollution increased COVID mortality

-Air pollution leads to hypertension, diabetes, obesity, and immune suppression all of which make someone more vulnerable to covid

-about 20% of Michigan COVID deaths could be attributed to air pollution

-shows that environment does impact human health

-could be a justice issue

Covid monitoring

-initial PCR tests were all reported

-deaths and hospitalizations tracked but these are a late indicator and only show severe infections

-in early pandemic, it’s estimated that cases were 2x higher than reported, in later pandemic it’s estimated cases were 24x higher than reported due to home tests, asymptomatic cases, or not bothering to get tested

-don’t have a good monitoring system with at home tests, early warning indicators are needed to take action

-this could be intensive monitoring of a representative subsample of the population

-sewage sampling

Omicron

-mutation in spike proteins makes it have higher transmissibility (Ro)

-less severe disease in not vulnerable populations, not as likely to infect lower respiratory tract and cause pneumonia

Vaccines

-In 2023, 3-5x more infection in unvaccinated, 4-6x more deaths

-Individual level

1. prevent severe infection, hospitalization, and death

2. strong, but not absolute, protection against infection

3. prevent long COVID and other post infection effects

4. receive protection of existing (blood and portal) antibodies, and memory B and T cells

-Population level

1. protection from all infections (including minor and asymptomatic) so virus has less chance to spread

2. Preventing infection is important because people are most contagious early in infection before memory responses kick in (importance of booster)

3. existing antibodies (blood and portal tissues) as first line of defense

Immune response to variants

-Mutations arise and are selected for ability to spread: infectivity, viral load, immune evasion

-These mutations often occur to the 3D shape of the spike protein to make it bind stronger to ACE2 or to evade antibodies

-This prevents antibodies from previous infections or mRNA vaccine from binding to spike proteins and preventing infection

-However, T-cells recognize the spike proteins linear structure, not 3D shape, and this mutates less

-So T-cells from earlier variants can still attack later variants and prevent severe disease. They are not as good at prevent disease though due to delay and not blocking infection.

-T-cells can also target other proteins such as N and RTC

-Memory B cells can also respond to later variants

Booster shot

-Israeli study showed much lower infection and severe disease rates for boosted vs vaccinated without a booster groups

-booster replenished existing antibodies in blood and portal tissues which act as a first line of defense against infection. The antibodies begin to wane after 3-6 months which is why a booster is important and it takes about 10 days to build up immunity. Even if existing antibodies fail to prevent infection, they could reduce initial viral load and reduce severity.

-as existing antibodies wane, memory cells remain. These are crucial for causing less sever infections, but not as effective at preventing infection because they have a response time.

Future Covid vaccine ideas

1. updated to create circulating antibodies for current variant

2. multiple strains in one vaccine

3. combined COVID/flu vaccine

4. nasal spray to create immunity directly in respiratory tract

5. targeted towards T cells

6. universal vaccine focused on unchanging part of spike protein between variants

Chemicals in Industrialized Society

-60,000-80,000 chemicals used

-1000 new chemicals every year

-chemical production is growing 2x faster than population

-only pesticides are required to be tested

-chemicals used for carpets, electronics, cleaning, toiletries, dyes, paints, pesticides, plastics, flame retardants

Industrial chemical history

-WW2: use of DDT to prevent malaria and typhus (discovered 1890s, used 1939), organochlorine insecticides, nerve gases (organophosphates)

-Chemical/industrial boom after war, better living through chemistry

Silent Spring

-Rachel Carson (1962), marine biologist

-Showed the acute and chronic effects of DDT and other chemicals on wildlife including acute mortality in robins and chronic reproductive effects in eagles

-helped launch the environmental movement of the 1960s

-not that we can’t use any chemicals, but we must be wise

-balance of nature is important

Our stolen future

-Theo Colborn (1996), pharmacist and then PhD in ecotoxicology

-Found a pattern in chemical exposures and effects while compiling literature for a book about the great lakes

-In 1991 gathered experts across fields to the wingspread conference where a scientific consensus on endocrine disruptors was created

-1996 wrote Our Stolen Future about endocrine disruptors and their effects on fetal development

Lessons from Carson and Colborn

1. People are being exposed to chemicals without their knowledge and non-target animals are also being hurt/killed

2. decisions about chemical safety were entrusted to the wrong people, risk assessment is needed

3. endocrine disrupting chemicals don’t cause cancer, rather they mess up the hormones that control development.

4. 1996 legislation mandating testing for endocrine disruption

Biomagnification

-An increase in the concentration of a chemical with each level of the food chain

-only some chemicals biomagnify, must be persistent and stored in tissues

-Halogenated chemicals biomagnify because carbon-halogen bonds don’t break down. Examples are F, Cl, Br bonds and specifically DDT, PCBs, and cyclodiene insecticides

-Methyl Mercury (Hg-CH3) biomagnifies because metals don’t break down and it’s stored in neural tissues

Bioconcentration, bioaccumulation, biomagnification

Bioconcentration: when an organism takes up chemicals directly from its environment (usually water), not through ingesting contaminated food

Bioaccumulation: the gradual build up of chemicals within an organism over time

Biomagnification: the increase in concentration of a chemical with each level up in the food web

Legacy pollutants

Persistant organic pollutants (POPs): chemicals that we have known the danger of for some time, many have been banned or restricted, however, they still remain in the environment in dangerous concentrations

-DDT, Aldrin, Mirex (organochlorine insecticides)

-PCBs (industrial chemicals)

-Dioxins and Furans (by products of chlorinated chemical production)

Contaminants of Emerging Concern (CECs)

Newer chemicals that are widely used and may pose a danger to human/wildlife health but lack rigorous testing.

-Flame retardants (PBDEs)

-industrial detergent

-plastics (BPA, pthalates)

-PFAS

-neonicotenoid insecticides

PFAS

-15,000 PFAS chemicals in use

-Perfluorooctane Sulfonate

-used for Scotchguard, fire fighting foam, food wrappings

-$300 million in annual sales

-Found in high concentrations in marine mammals, fish, birds, and humans

-travels through water

-stored in fats

-toxicity is uncertain, some has been voluntarily withdrawn from use

Ecotoxicology

The study of the harmful effects of chemicals upon ecosystems, to include effects upon individuals as well as consequent effects at the levels of populations and above.

-environmental toxicology is similar but focuses on the effects of environmental contaminants on humans

Six ways to bend science

1. Shaping science by creating research to show a desired outcome

2. Hiding science associated with unwelcome information

3. Attacking science with illegitimate critiques to present reliable science as “junk”

4. Bullying and harassing scientists who produce unwelcome information

5. Packaging science by assembling an expert group to advance a favored outcome

6. Spinning science by manipulating public perception of credible science

Precautionary principle

Regulating chemicals that have a suspected risk of harm to the public even if complete scientific evidence is not yet available. This can prevent the harm that may otherwise occur in the time it takes to conduct studies.

-Puts the burden of proof on companies to prove safety.

-Common practice in EU law

-Critics argue it’s overly cautious and stifles innovation, it could lead a chemical to be replaced by a more dangerous one, and could lead to political decisions that lack a strong basis

Endocrine disruptors

Chemicals from outside the body that interfere with the normal functioning of hormones (transport, release, binding, elimination) that control normal development and function in organisms.

Can affect reproductive, thyroid, stress hormone, immune system, etc.

They pose potential significant health effects because hormones work at very low concentrations, so endocrine disruptors could cause effects at very low doses. Especially during pregnancy, exposure to disruptors could interfere with development and lead to life long consequences

Normal hormone response

-Hormone binds to a receptor and stimulates a response

Ex: in female birds in the spring, estrogen levels increase, the hormone travels from the ovary and binds to a receptor in the liver which switches on production of a protein to produce eggs

Mimic disruptor

-A mimic or agonist chemical fits into a hormone receptor and stimulates a response.

-This is seen in the feminization of fish downstream of a sewage treatment plant

-the water had synthetic estrogen in it which binded estrogen receptors on host cells in the fish and caused production of a egg protein

Blocker Disruptor

-A blocker or antagonist disruptor binds with a hormone receptor site but doesn’t stimulate a response and prevents the actual hormone from binding

-A testosterone antagonist would fit into the testosterone receptor and block testosterone from binding

Why endocrine disruption is hard to study

-can’t do ethical lab studies on humans

-very low doses can cause problems while higher doses may not

-a combination of chemicals can be the problem

-effects often only show up in offspring

Atrazine

1. herbicide used for corn and other crops

2. it inhibits photosynthesis in plants

3. leading source of money for Syngenta

4. Found ubiquitously in surface waters

5. It may be toxic to amphibians and humans

6. Banned in the EU but reregistered by US EPA

Hayes’ study

-raised frogs in the lab

-the frogs exposed to atrazine produced very little testosterone and were intersex

-frogs in the wild exposed to atrazine also were intersex

-frogs raised in the lab with field sample water also had intersex features

-Study showed that very low doses had a negative impact, but higher doses had a smaller impact - non-monotonic response

-raises questions about chemical safety laws

Monotonic vs non-monotonic dose response curve

-In a monotonic dose response, the measure of the dependent variable moves in one direction as dose increases (such as linear)

-In a non-monotonic dose response, the value of the dependent variable does not consistently either increase or decrease

Sperm studies

-Swan found that men in rural city had lower quality sperm

-Swan found that men exposed to more pesticides had lower quality sperm

-Study reanalysis determined that sperm concentration has been declining, especially in western males

-exposed through drinking water, makes us think more about what chemicals are in our environment

Colborn lessons

-not just cancer

-biomagnification: species at the top of the food web have high exposure

-hand me down poisons: chemicals in females harm offspring, even in very low doses

Atrazine and sex hormones

-Cholesterol is a precursor to steroid hormones

-Enzymes act on cholesterol to produce testosterone

-Aromatase turns testosterone into estradiol

-Females generally have high aromatase levels to convert most of their testosterone to estradiol

-In frogs, atrazine increases aromatase activity causing much more testosterone to be converted into estradiol

Rohr conclusions

-science can be shaped, attacked, hidden, bullied, packaged, and spun

1. do science right (unbiased and no politics) before making decisions

2. peer review important (not chemical industry studies)

3. scientific community can sort out good and bad but takes time

4. good scientists in government can do good things if funded and empowered

5. standards can be used to weigh data

6. independent review panels are important

7. scientific consensus statements

Belugas

Belugas in the St. Lawrence River were found to have lots of cancer and lots of chemicals in them. Study found that combinations of chemicals could be more harmful than those chemicals by themselves. This makes us rethink RAs that often look only at 1 chemical. Daunting task because there are thousands of chemicals and even more combinations.