Viruses and Disease: Week 1

Week 1: Viruses and Disease

• Avian influenza virus (AIV) affects mostly aquatic birds.
• Hemagglutinin leads to clumping of red blood cells.
• Neuraminidase inhibits hemagglutination by cleaving sialic acid.
• New vaccines are needed each year due to ongoing mutations and adaptations in viruses.
• Alzheimer’s disease results from aggregated tau protein, causing neurofibrillary tangles.
• Antigenic drift: Gradual mutations leading to adaptations and variations in viruses.
• Antigenic shift: A sudden change in a virus's genetic makeup, creating a new strain.
• Arms race: The immune system learns from pathogens, and pathogens learn about the immune system
• Bacterial food poisoning is not from a single agent.
• Gastroenteritis: Characterized as stomach flu, which can lead to long-lasting diarrhea.
• Symptoms are not the same in every case, loss of fluids is common.
• Beaver fever is a pathogen found in mountain stream water.
• Broad specificity pathogens can infect a wide range of host species.
• Adhesive fimbriae on bacterial surfaces bind to glycoproteins and glycolipids on cell surfaces.
• H1N1: A strain that caused the Spanish flu and today's swine flu.
• Corona Sars-Cov-2: Its viral spike (S) protein binds to ACE2 cell surface receptors.
• It could have bats and pangolins as intermediate reservoirs.
• Ebola virus is a negative-strand RNA virus with fruit bats as reservoirs.
• It's highly transmissible and causes hemorrhagic fever.
• An organism at biochemical equilibrium is dead.
• First law of bio: All living organisms obey the laws of thermodynamics

Week 1: Immunology vs Pathogens

• Life requires the creation of order (decreases entropy)
• An organism at biochemical equilibrium is dead.
• HIV is a human immunodeficiency virus, specifically an RNA enveloped lentivirus.
• HIV has a very high mutation rate due to its retrovirus mechanism (faulty RTase).
• Homology: Descent from a common ancestor.
• Stopping the spread of BSE involved banning certain animal parts from entering the food chain.
• Marburg spreads to humans through consumption of bushmeat or direct contact.
• Pigs possess two receptors: one binds avian viruses, and the other binds human viruses.
• Influenza viruses evolve rapidly because multiple viral chromosomes allow recombination when infecting the same cell.
• Influenza is usually a negative-sense single-stranded RNA virus.
• Kuru was spread among people who practiced cannibalism.
• Marburg Virus: An enveloped RNA filovirus that causes hemorrhagic fever.
• Marburg is transmitted through contact with or ingestion of bats or green monkeys.
• MERS (Middle Eastern Respiratory Syndrome) needs an intermediate host, most likely a camel, and its transmission was relatively limited.
• The most common protozoan food poisoning agents are toxoplasma, cryptosporidium, and giardia.
• The most important pathogens for foodborne illnesses are bacteria, viruses, prions, and protozoans.
• Most influenza viruses appear to be avian in origin.
• Natural selection appears at both phenotypic and genotypic levels.
• Non-human primates are susceptible to HIV and Zika virus.
• Noroviruses are common in oysters and seafood.
• Physical laws dictate that no system can exhibit perpetual motion.
• Pigs are a massive location for viral recombination.
• Prion diseases are transmissible spongiform encephalopathies (TSEs) or protein aggregates.
• Prion diseases cause other normal proteins to fold incorrectly, like a chain reaction.

Week 1: Biology Laws and Swine Flu

• BSE led to mad cow disease.
• Peyer's patches in the intestinal tract of cows are where major prion proteins can be found.
• Prion diseases cause cellular protein to shift from a correct alpha-fold to an incorrect beta-fold.
• Second law of biology: All life is enclosed in membranes.
• First corollary: The cell is the only structure that can grow and divide on its own.
• Second Corollary: All life is programmed by cellular genetics instructions.
• Swine influenza virus has pigs as hosts.
• Pigs have 2 receptors for viruses.
• Pigs can swap their genetic material and create more virulent strains, considered mixing bowls of influenza virus.
• First two laws of thermodynamics:
• Energy cannot be created or destroyed.
• Entropy of a closed system always increases.
• RNA-dependent RNA polymerase lacks a good proofreading capability.
• Third law of biology: All living organisms arose in an evolutionary process.
• First corollary: all living organisms have homologous macromolecules
• Second corollary: Genetic code is universal for all organisms.
• Influenza is transmitted from bird to pig to human.
• Viral food poisoning is less common but most costly to detect and hardest to treat.
• Virus recombination can occur.
• Rotavirus can cause gastroenteritis.
• Norovirus can cause gastroenteritis.
• Bats are often the original host.
• Virus recombination is when two related viruses in the same host mix genetic material, becoming more virulent.
• Bats, primates, and rodents have a higher proportion of zoonotic diseases.
• AIV refers to Avian Influenza Virus.
• Mad cow disease is a mutated human variant of BSE.
• Gram-positive bacteria is the most common type of bacteria for food poisoning.
• RNA viruses evolve faster than DNA viruses because RNA is less stable, and DNA has access to host proofreading.

Week 2: Amino Acids, Genetic Diversity, and Metabolic Pathways

• P2 is most important for determining the type of amino acid.
• P1 is important for the specific amino acid
• Negative selection principle states that changes to the least important elements are most likely to occur.
• Alternate wheel based on P2 has 4 quadrants: hydrophobic (T/U), hydrophilic (A), and 2 semi-polar (Gorc).
• Similar amino acids will likely only vary in one position.
• Wobble base pairing: P3 allows specific alternate base pairing.
• For start codon (fMet/Met), wobble is P1.
• When P3 is important, it only matters whether the position is a purine (A or G) or pyrimidine (U or C).
• More H-bonds can be formed between C+G than A+U.
• Bonds between tRNA + mRNA are stronger when the tRNA is a purine, and mRNA is a pyrimidine.
• All common nonsense codons use U in P1.
• The most common stop codon, UAA, has the lowest H-bonds possible out of all possible stop codons.
• Primordial soup conditions can also give rise to nucleic acids, lipids, and other molecules.
• Benefit of redundancy: Multiple codons can code for the same amino acid, a SNP has less chance to change the amino acid identity and cause a problem.
• Eukaryotes branched off from asgard archaea.
• Episymbiosis: Understudied mode of association between microbes, especially for CPR bacteria + DPANN archaea.
• No cell is an island: genome-resolved metagenomics approaches allow for studying metabolic pathways spanning different species in a community
• Asgard archaea was found in seafloor sediments near hydrothermal vents.
• Asgard genomes typically encode eukaryotic systems.
• MVA lipid synthesis pathway
• Membrane remodeling / trafficking systems.
• Cytoskeletal proteins
• Ubiquitin.
• Vesicle formation systems.
• CPR: Candidate phyla radiation.
• CPR and DPANN are mostly symbionts and episymbionts.
• Episymbiont: Symbiont that lives on the surface of another organism for survival.
• Radiation: Increase in taxonomic diversity caused by elevated speciation rates.
• CPR bacteria lack key biosynthetic pathways.
• Classify based on metabolic insights, metagenomics.
• Different environments create lineages that diverged early from primitive life forms.
• Bacteria of CPR consistently have small genomes and cell sizes and most have a symbiotic lifestyle.
• DPANN Archaea are small cell sizes with limited metabolic abilities and unique surface attaching grasping hooks (hami)
• Non-CPR bacteria can mix aerobic + anaerobic pathways, metabolic versatility & can survive in changing conditions.
• Non-CPR bacteria exist in our microbiome and perform fermentation, not photosynthesis.
• Secondary metabolites from non-CPR bacteria can give insight into lineages.

Week 2: Genetics and Metabolic Insights

• CPR and DPANN archaea have slightly different genetic codes.
• CPR and DPANN archaea also have unusual ribosome compositions, possibly missing some "essential" ribosomal proteins.
• Gaps in genetic codes are often shared.
• Gaps are not shared well with non-CPR symbiotes.
• Episymbiosis is common for CPR and DPANN.
• Episymbiosis is associated with the surface of cells, allowing for cell-to-cell contact.
• Pili-like structures extend from CPR cell surfaces.
• Asgard archaea share a relatively close evolutionary relationship with eukaryotes, from which scientists then saw a fusion of bacterial and archaea cells.
• Many archaea genes are considered eukaryotic signature proteins.
• There is a lipid divide, where isoprenoids are essential metabolites in all living organisms in all domains of life.
• Archaea membranes consist of isoprenoid-based lipids, made with the MVA (mevalonate) pathway.
• MEP pathway: alternate MVA pathway used by eukaryotes and archaea
• MEP is not widely reported in archaea.
• Lipid divide between bacteria and archaea, with differing MVA and MEP distribution.
• Everything is made, consumed, and digested.
• GABA: gamma-aminobutyric acid.
• Lingering questions exist, such as those around rapid evolution.
• Reduced genomes tend to increase evolution rates.
• Early divergence raises the question of not having enough of the missing links.
• Convergent evolution exists.
• The genome-reduced symbionts are mostly ruled out by non-overlap with non-CPR (like buchnera).
• Horizontal gene transfer allows organisms to "borrow" systems from other lineages.
• BBB: blood-brain barrier.
• ASD (autism spectrum disorder) is highly multi-factorial.
• There's a connection between gastrointestinal (GI) issues and ASD.
• Gut microbiota are important.
• The microbiome strengthens intestinal barrier integrity.
• Microbiota development starts at birth.
• The intestinal barrier can directly or indirectly affect homeostasis.
• Growing evidence shows that dysbiosis can cause several diseases and disorders, such as ASD.
• Metabolism: Microbiota produces many metabolites.
• Short-chain fatty acids (SCFAs) can act on the CNS through the microbiota-gut-brain axis.
• Tryptophan can be converted into metabolites that generate neurotoxic products depending on changes to the microbiome.
• ANS: automatic nervous system.
• ENS: enteric nervous system.
• HPA: hypothalamic-pituitary-adrenal axis.
• ANS, ENS, HPA communicate via the vagus nerve to mediate the gut-brain connection.
• Neurotransmitters (NTs):
• Metabolites from microbiota cross the BBB + change levels of NTs.
• GABA is not able to cross the BBB + only acts locally.
• Maternal microbiota is also important:
• Maternal gut microbiota modulates growth & fetal brain development.
• Vertical transmission of microbiomes, birth method can have significant differences in microbiome diversity.

Week 2: Genetics, Microbiota and BBB

• Epigenetics are important.
• Epigenetics change acetylation & deacetylation.
• Deacetylation results in gene inhibition by condensing the chromatin.
• Histone deacetylases (HDACs) are targets of microbiota-derived metabolites.
• ASD postmortem brain samples show abnormal alternative splicing of mRNA.
• BBB is relevant because:
• Maternal gut microbiota influences the fetal BBB.
• The maternal gut microbiota can upregulate the expression of tight junction proteins.
• Food selectivity: picky eating and severe food selectivity (FS) in ASD patients.
• Consumption of particular diets alters gut microbiota to favor specific bacterial genera.
• Less diverse diet could reduce microbiome diversity.
• Social interactions are affected as deficits in social behavior can be reversed by probiotics and microbiota recolonization.
• Germ-free (GF) animals are affected: GF mice have social behavioral problems compared to normal mice.
• Probiotics are species of live microorganisms that provide health benefits to the host upon ingestion.
• Prebiotics: Non-digestible fiber compounds that act as a substrate for the growth of beneficial microbes.
• Synbiotics: Contain a combination of specific probiotics and suitable prebiotics that may produce similar beneficial effects in ASD.
• Fecal microbiota transplantation (FMT): When given to children, ASD symptoms are greatly reduced, as well as GI problems.
• Biomarkers include butyric acid, a short chain fatty acid (SCFA), that has a proinflammatory function of intestinal macrophages that regulate BBB permeability.
• Zonulin levels: Gut tight junction-stabilizing protein was upregulated in ASD children.
• Therapeutics includes noting that no universal treatment has been discovered yet, with significant heterogeneity between cases.
• Microbial products cause differences in neurodevelopment.
• Excessive inflammatory products, like IL-6, can cause abnormal neuron outgrowth and retardation.
• Inhibiting IL-6 has reversed abnormalities in offspring prenatally exposed to maternal immune activation (MIA).
• Normal microbes are required for the upkeep of the intestinal lining tight junctions, which can inhibit IL-6.
• Altered BBB allows inflammatory cytokines + causes neuroinflammation.
• Many kids with autism suffer from various GI issues, such as IBD + Crohn's disease.
• Disruption of the mucosal microbiota has been extensively reported in ASD children.
• "Leaky gut" is where cytokines from the gut can get into the bloodstream & then pass the BBB.
• Cooperation may be the true driving force for survival + evolution.
• Plastids in plants + microbiota in most major eukaryotic subdivisions arose via initial endosymbiotic events from cyanobacteria + proteobacteria.
• Bacterial parasites:
• • B. bacteriovirus: Bba -- B. exovorus: Bex
• Parasitic modes:
• • Bba grows in peraplasm of the prey cell
• • Bex grows externally
• Both Bba & Bex contain large numbers of pseudogens & incomplete systems.
• Bba life cycle:
• • 1. attack
• • 2. outermembrane penetration
• • 3. periplasmic growth phase (no division)
• • 4. final synchronous cell division stage together w/ a host cell lysis
• Betelloplast is the single snake-like multi-nucleoid cell.
• Bex grows completely outside the cell.
• Bex grows + divides by binary fission.
• Bex has a smaller genome than Bba.
• Symbiotic archaeal species include:
• • nanoarchaeum equitans: A novel small type of archaeon was discovered in apparent symbiotic relationship w/ different, larger sized, archaeal species
• • can only co-culture w/ Ignicoccus species
• Metagenomics + CPR is imporant because CPR has self-splicing introns

Metagenomics, The Laws Of Biology and Prokaryotes

• Metagenomics restated: the DNA of entire communities of bacteria simultaneously sequenced w/o separation of different species.
• Asgard exhibit small cells depend on cooperative symbiotic relationships
• Reverse flow model: updated symbio-genetic model involves electron or hydrogen flow from organoheterotrophic archaeal host to bacterial symbiont.
• There's much greater diversity of the bacterial domain, suggesting that bacteria were first inhabitants Earth.
• No primordial life form could have a full complement of metabolic and biosynthetic catalytic proteins, allowing them to reproduce without relying on only abiotic sources.
• Genetic Recombination + interspace gene transfer, mediated by transposons + plasmid-like elements
• Since evolution tends to complexity, suggested symbiotic relationships provide a potential pathway for creation of more complex organisms
• Darwin is given credit for the 3rd law of biology
• Entropy of a closed system always increases
• Viruses can use RNA
• DNA is much more stable, a good tradeoff
• CPR nano-bacteria + nano-archaea look similar
• Both CPR and nano-archaea is:
• • associated w/ much larger microbes
• • episymbionts
• • small genomes & small size
• Obligate: must be a certain way, versus facultative, which has preference but can survive in either
• Aerobe: oxygen-dependent, while anaerobe oxygen-independent
• In terms of oxygen:
• • Obligate anaerobe: no growth in oxygen
• • Obligate aerobe: growth in oxygen
• • Facultative anaerobe: can grow w/o oxygen, but prefers having oxygen
• • Facultative aerobe: can grow w/ oxygen, but prefers no oxygen
• Lamarck: Soft inheritance or lamarckism with First theory of acquired characteristics
• Use and disuse are phenotypic characteristics.
• When certain organs become specially developed as a result of environmental need, that is hereditary and can be passed on to progeny.
• Bioinformatics: every detail of organism is encoded, deciphered + rendered
• Evolution is a guide through which biology makes sense
• Molecular phylogeny is most reliable guide for function + mechanisms & phenotype
• The microbiome is multiple microbiomes, one in each tissue.
• Each tissue microbiome influences health + activity of the tissue
• Innate immune system: fast + general, adaptive immune system: slow + specific
• The immune system may accidentally kill commensal bacteria when trying to kill pathogenic
• Beneficial = commensal / Virulent = pathogenic
• The microbiome reinforces barrier immunity of the host
• Host minimizes contact between microbes + the epithelial surface to limit inflammation
• Mucosal firewall formed to keep invaders out -- Mucus line is first defense against pathogens -- Antimicrobial peptides produced from epithelial cells are second defense -- Macrophages are third line of defense
• Microbiota is highly dynamic.
• Density correlated w/host immunity
• Microbiota protects from inflammatory disorders
• Microbiota also acts via GBA (gut brain axis)
• Human gut -If system breaks down, one can end up w/ inflammatory diseases like IBD and is multifactorial -- Changin microbiota causes inflammation and disease that affects the gut again
• Diet, microbiota, immunity = interdependence triangle
• The Gut lumen: lumen is inside space of tubular structure like artery or intestine, which means opening
• Gut brain axis: biochemical signaling between GI tract and ENS + CNS
• It is all connected via the vagus nerve
• BBB helps keep brain free of pathogens

Purines to Probiotics

• Tthe right junctions of blood vessels in the brain are part of the BBB
• Glial cells surround blood cells in BBB
• Immune system in brain is different than rest of body
• dietary + environmental stress alter Gl microbiota
• 80% of serotonin is made in gut while 20% is made in brain
• some microbes make metabolites like butyrate, which can alter activity of cells in BBB
• IL-6 affects stress levels
• Purines have 2 aromatic rings & pyrimidines have only 1 such ring
• not all A:T binding or C:T binding are equivalent in energy
• The variable position of P2 has the least amount of variance
• Key Positions =
• P2 specifies type of amino acid :
• T=hydrophobic
• A= hydrophilic
• CtG= semipolar
• PI specifies identity of amino acid
• P3 is wobble position, except in initiation
• for initiation, wobble is Pl not P3
• Termination:
• all U to start
• pyl= pyrrolysine
• sec= seleno-cysteine
• leucine is most resistant to non-synonymous mutations
• Pyl in archaea + bacteria
• sac is in all domains of life
• --A:T + T:A, G:C + C:R
• -Depends what is the tRNA of what is the MRNA?
• -T:A= MRNA:tRNA is stronger that other way around
• -C:B = MRNA:tRNA is stronger
• --There are eukaryotic-like genes that are found inside archaea
• --eukaryotic specifies proteins
• Most aerobic-like pathways found in nanobacteria are obligate anaerobes + cannot to levato oxygen
• MVA in archaea/eukaryotes, MERP in bactria. there is a Lipid divide, But Sporadic exceptions exist
• Mutations is the most important, however cooperation can be importnat as competition
• Huge diverse in microbial life
• Prokaryotes complete C,N,S fixation cycles
• Decomposition and photosynthesis
• Species specif interactions such as mutualism
• 3 maninhouses Gases:
• -Carbon Dioxide
• -Nitrous Oxide
• -Mathane