Lecture 29- Adaptive Immunity, Avoiding Immune Response, Bacterial Pathogens

Molecular Arms Race between…?

the immune system and pathogens, due to evolution, exposure, and intervention

Extracellular pathogens can…?

counteract the immune system

Extracellular Pathogens can counteract…?

the immune system

Extracellular Pathogens

microbes that reside outside or on the surface of the host cells or in the medium

Extracellular Pathogen Production

produce toxins and other enzymes that help them avoid or fight the host immune system

Mucus Layer

penetration helps evades the host defenses, physical and chemical barrier to microbes

Bacteria Penetration to the Mucus Layer

bacteria that have flagella and/or lack sIgA binding surface components more easily penetrate mucus without getting trapped

Bacteria and sIgA proteases

bacteria can secrete sIgA proteases that can cleave sIgA to prevent trapping and sloughing of the pathogen

sIgA Evolutionary Trade off in Pathogens and Humans

1) the resp pathogens S. pneumoniae and Haemophilus influenzae secrete sIgA proteases to allow escape from mucosal epithelium

2) human colostrum sIgA is resistant to cleavage by these sIgA proteases, protects newborn hosts

Defensins

cationic positive charged antimicrobial peptides, creates pores in bacterial membranes

Gram Negative Bacteria Protection and Surfaces

by their negatively charged LPS, which bind the cationic peptides and prevent them from reaching the bacterial membrane surfaces, other bacteria decorate their surface with - charged sugars or other similarly charged molecules

Gram Negative Bacteria, Protection and Proteases

some have periplasmic proteases that degrade the defensins before they reach the inner membrane

Evading Host Defenses by Resisting Complement

1) some pathogens bind, cleave, or look like parts of complement system to avoid opsonization

2) some pathogens mimic host surfaces to evade immune recognition by decorating with host like sugars or proteins

3) gram neg bacteria have altered LPS structures that don’t bind complement or don’t form MAC, so they are resistant to killing by MAC

2 Ways of Resisting Immune Recognition

1) antigenic variation

2) phase variation

Antigenic Variation

permanent genetic change through mutagenesis, gene conversion, gene swapping, and homologous recombination that change surface components

Phase variation

another way to resist immune recognition through switching or turning genes on or off, so the microbe or virus is not recognized by host immune cells

Example of Resisting Immune Recognition

vaccines against STD causing Neisseria gonorrhea don’t work, even though antibodies are produced they only work against 95% of the microbes against which they’re elicited, by the time an adaptive immune response is mounted 5% of the Neisseria population has undergone antigenic variation so the antibodies no longer recognize the bacteria, so a protective immune response never acquired and reinfection can occur, the only way to clear is thorugh antibiotics

Resisting Opsonization and Phagocytosis

1) capsules

2) binding to Fc portion

Capsules

layer of polysaccharide or polypeptide outside of cell wall difficult to degrade and block complement activation to prevent phagocytosis

Binding to Fc portions

some bacteria have proteins on their surfaces that bind to Fc portion of IgG so the bacteria coat their surfaces with IgG so that phagocytes with Fc receptors can’t recognize antibodies or opsonize

Examples of Resisting Opsonization and Phagocytosis

protein A of S. aureus and protein G of S. pyogenes bind to IgG in wrong direction

Example of Evading Host Defenses in S. aureus

S. aureus:

1) protein A, and capsule blocks complement activation and phagocytosis

2) fibronectin and collagen binding protein, it coats surface with host proteins looking like “self” to host

3) binding IgA and complement avoids phagocytosis, degranulation, and complement activation

4) clumping factors, bacteria clump together to help avoid phagocytosis, binding fibrinogen helps look like host

Intracellular pathogens

microbes that can enter, survive, and reside in the host cell, hide from pathogen by invading, surviving, and residing in the host cell

Intracellular Pathogen Host Evasion

can prevent host cell immune responses and other mechanisms to kill them

Invasins and Internalins

bacterial surface proteins afimbrial adhesins bind to host cells and are able to provoke phagocytic uptake of bacteria by nonphagocytic host cells, not all bacteria that are able to attach can invade and not all that attach and invade are able to survive in the host cell

3 Advantages of Invading Host Cells

1) protection from complement and the humoral immune system

2) access to nutrient sources

3) transport to other sites, dissemination and spread

Protection from Complement and Humoral Immune System, Advantage

antibodies and complement don’t work inside cells, they are extracellular

Access to Nutrient Sources, Advantage

host cytosol rich in nutrients, if access can be gained, microbes can thrive in this area they are not normally allowed access

Transport to Other Body Sites, Advantage

the bacteria inside a host immune cell can travel along the immune cell to underlying tissues and rest of body through blood or lymph system

Phagosome

membrane vesicle that enclosed the bacteria that have been engulfed and taken up by host cells, usually fuse with lysosome to make phagolysosome

Phagolysosome

release toxic lysosomal contents and kill the bacteria

Some pathogens have developed…?

ability to survive and replicate inside phagocytes by evading degradative process in phagolysosome by preventing phagolysosome fusion, escaping the phagosome, and lysosome neutralizing factors

Preventing Phagolysosome Fusion

this then allows formation of specialized bacterium containing vacuole where the bacteria can replicate

Escape from the phagosome

escape into the cytosol by pore forming or membrane disrupting toxins

Lysosome neutralizing factors

used to survive in the phagolysosome, some pathogens have altered cell membranes LPS or have capsules resistant to defensins, lysosomal proteases lysozyme, some produce catalase enzyme and other enzymes that neutralize lysosomal reactive oxygen and nitrogen species

Salmonellosis

food borne pathogen, severe human and animal disease by Salmonella enterica

S. enterica entering

through intestinal enterocytes, m cells and associated macrophages of Peyer’s patches, invades macrophages and prevents phagolysosome fusion and survives and replicates in specialized salmonella containing vacuoles

Listeriosis

food borne pathogen, severe human and animal disease by gram pos Listeria monocytogenes

Listeria Monocytogenes Entering

when bacteria enters host cell, they secrete pore forming and membrane degrading toxins enable bacteria to escape into the cytosol, escape phagosome and lyse vacuoles to enable cell to cell spread