1-1. Medicine II_Host and Microbes 2014A

July 23, 2012

Host and Microbe Dr. Mario Panaligan

INTRODUCTION 

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Infection is a problem that won’t go away. Around a century ago there was a discovery of a drug against syphilis. It was predicted that infection would be eradicated. However, microbes have exhibited a great  ability to adapt, survive, and challenge and thereby become resistant to several anti-microbial agents. Although there has been a dramatic decrease in  communicable diseases in developed countries through immunization, improved nutrition, sanitation  and housing. Certainly, infections remain a major cause of death. About 1/3 of all deaths are caused by infection. Host-microbe relationship: exploitation by an organism (microbe) of the environment provided by another (host).  Eliminated Diseases (these can be agents for  biological warfare)  o Smallpox  o Polio o Most cannot be eliminated in our lifetime because of the ability to mutate, adapt, and continue to grow Emerging Diseases: in the last 30 years, 30 new diseases have emerged  o HIV o Ebola virus o Cryptosporidiosis o SARS Re-emerging Diseases: once thought to be eliminated o Influenza o Tuberculosis o Malaria  o Cholera o Diphtheria

DEFINITION OF TERMS 

Infection - establishment of a microorganism on or within a  host; may be short-lived, most often asymptomatic, or subclinical signs of altered pathophysiology.

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Infectious Disease - signs and symptoms result from its associated damage or altered physiology due to the  invasion of an organism o

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Pathophysiologic state of the host that may manifest with clinical signs and symptoms, usually due to the damage caused by the interaction between the host  and the microorganism

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Outcome is determined by the immune status of the host

BEHAVIORAL AND SOCIAL CHANGES THAT INCREASE PATHOGENICITY OF MICROBES Altered environments (usually the seasons of the year; i.e. during the rainy season we see a rise of dengue and even leptospirosis) Changes in food production and food handling practices (i.e cholera and typhoid fever) Antibiotics and immunosuppressive therapy o Antibiotics can lead to collateral damage leading to the emergence of resistant pathogens o Immunosuppressive therapy causes a burden to human primarily because Altered sexual habits have led to the rise of many STDs Breakdown of filtration systems (contamination) Increase in ownership of pets, esp. exotic species Increase in travel (all 4 strains of dengue are now in the Philippines because of increase in travelers bringing the virus)

NORMAL FLORA ADVANTAGES Prevent overgrowth of pathogenic organisms o Skin: fatty acids o Gut: Release bacteriocins, colocins, and metabolic waste; Compete with others for living space, produce Vit B and K o Vagina: lactobacilli maintain acid pH

DISADVANTAGES Potential for spread during procedures or trauma may lead to bacteremia o Intestinal perforation o Skin breaks o Dental extraction Person is vulnerable during periods of decreased immunity, change in environmental conditions

MAN-MICROBE RELATIONSHIP Colonization

(symbiotic) - simple presence of potentially pathogenic microbes in or on a host [Harrison’s] Normal flora will remain symbiotic as long we maintain good hygiene Disease-causing property: o Distribution o Pathogenicity o Host defense Common pathogens: early immunity There is what we call early immunity which protects us from subsequent reinfections o

Pathogen - any microorganism that has the capacity to cause disease Virulence - quantitative measure of pathogenicity or likelihood of causing disease  o Opportunist - microorganism that cause disease in immunosuppressed persons or those with underlying chronic disease (ex. COPD, MICROBE-HOST INTERACTION: EFFECT ON HOST CKD, DM etc.) ACUTE CHRONIC o Microbes with a capacity for sustained multiplication  Fever  Weight loss and muscle in human without causing a disease to healthy ones. Page 1 of 11

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Inflammation  Convulsion in children  Shock Hemorrhage Organ failure: kidney,  liver, lung, heart, brain,   skin necrosis

wasting  Malnutrition esp. diarrhea Growth retardation in children Anemia Tissue destruction Post infective syndromes

External behavior o o o

PATHOLOGY OF INFECTION MICROBE MEDIATED  Direct cell destruction:  rabies, poliomyelitis, hepatitis   Exotoxin: tetanus,  cholera, botulism, diphtheria   Endotoxin: typhoid Gram  (-) septicemia, meningococcal infection

 HOST MEDIATED Neutrophils and macrophages Complement activation Activation of clotting cascade Immune mechanisms  Secondary autoimmune mechanism

MICROBIAL PATHOGENIC ATTRIBUTES   

factors:

Geography,

environment,

Geography/environment - P. falciparum malaria-bearing Aedes mosquito in mountainous and coastal areas Geography - antibiotic-resistant malaria are common in highly endemic areas (Phils, Africa, Indonesia) Behavior - acquisition of sexually transmitted diseases, IV drug use hepatitis B and C

Genetics: eg MHC genes (class II and leprosy), sickle cell gene, and malaria Specific host factors: Age (infants and elderly – altered immune response), immunization history, prior or coexisting illness (diabetes), nutrition (malnutrition), pregnancy, emotional state (depression), stress, hormones Medical care may increase risk of infection o Nosocomial pathogens, breaks in skin or mucosal surfaces, foreign bodies, altered normal flora, immunosuppression

Susceptibility

Pathogenicity: potential of a microbe to cause disease Virulence: degree of pathogenicity Factors promoting virulence: o Attachment to cell membrane  o Toxin production o Avoidance of host defense 

First encounter - initial encounter between a susceptible host and a virulent organism frequently results in disease, some organisms can be harbored in the host for years before disease becomes clinically evident. [Harrison’s]

Breach of barriers: especially in those patients with indwelling catheters Immunodeficiency: particularly those with underlying malignancies and those who underwent transplantation and are receiving immunosuppressive medication to prevent rejection

[Old Trans]: 1. Microbes have an intermediate group of complementary genetic properties that promote interaction to its host. This is the form of “genetic traits” called phenotypes. 2. Microbes should have the capacity to breach normal host anatomic, cellular or biochemical barriers that ordinarily MOLECULAR MECHANISMS OF MICROBIAL prevent entry by other microorganisms. (Motility, PATHOGENESIS [Harrison’s] chemotactic factors and adhesive structures) 3. Microbes are able to pass thru the “normal host defenses” 1. Microbial entry and adherence – the microbes must first with the following microbial factors: encounter the host then attach to it. a. Antiphagocytic capsule 2. Microbial growth after entry – after attachment and b. Elaboration of toxins and enzymes establishment, growth and replication must ensue c. Immune specific proteases and iron (IgA protease 3. ofAvoidance of Innate host defenses – once growing and Haemophilus influenza) inside the host, microbes must evade the host defenses d. Iron sequestration mechanisms (Neisseria 4. Tissue invasion and tropism – if successful at evasion and gonorrhea) there is continued growth, invasion and tropism may occur e. Avoidance of Phagocytosis by: 5. Tissue damage and disease – if the microbe is able to - Release toxin that destroys phagocyte establish itself in its niche and produce its products, then - Prevent opsonization by releasing protein diseases ensues - Prevent contact by capsule, etc. 6. Transmission to new hosts – microbial shedding from the - Inhibit fusion of phagolysosome host - Organism escapes into the cytoplasm and replicates within the phagocyte MICROBIAL ENTRY AND ADHERENCE - Resists killing by producing antioxidants, etc. Microbial Entry/Modes of Spread 4. Microbes have the ability to multiply upon reaching its specific niche (blood, lungs, and tissue) and the potential  Initial interaction of a pathogen with its host to be transmitted to a new susceptible host. (Malaria, HIV –  Route to invasion by intracellular parasites blood; TB – lungs; Parasites – tissues)

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HOST FACTORS INVOLVED IN THE DEVELOPMENT OF INFECTION

First step in host cell killing and toxin delivery

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Microbial entry usually relies on the presence of specific factors needed for persistence and growth in a tissue.

for microbial binding and entry into the target cells. [Harrison’s]

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Examples: pili/fimbriae, flagella, hemagglutinin, surface glycoprotein, glycosaminoglycan, viral capsid protein, lectins and lipids

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Fecal-oral spread via the alimentary tract requires a biologic profile consistent with survival in the varied environments of the [Harrison’s]: gastrointestinal tract – low pH of the stomach and the high bile content of the intestine; Viral Adhesins contaminated food or water outside the host.

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Entry via the respiratory tract – survive in small moist droplets produced during sneezing and coughing.

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Venereal routes – survive best in the warm  moist environment of the urogenital mucosa and have restricted host ranges (e.g., Neisseria gonorrhoeae, Treponemapallidum, and HIV).

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All viral pathogens must bind to host cells, enter them, and replicate within them. Viral coat proteins serve as the ligands for cellular entry, and more than one ligandreceptor interaction may be needed Examples: o

ROUTES OF ENTRY: 

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Contact o Measles virus H glycoprotein binds to both CD46 o Person to person – skin or mucous and the membrane-organizing protein moesin membrane, eg scabies, STDs on host cells. o Soil – wounds or abrasions, eg tetanus, mycetoma o Water – leptospirosis, schistosomiasis Air borne o Droplet or dust – measles, rubella,Bacterial Adhesins whooping cough, URTI, SARS o Fecal/oral spread – salmonellosis, bacillary Pili or fimbriae are commonly used by gram-negative and amoebic dysentery, hepatitis (and gram-positive) bacteria for attachment to host cells o Transplacental – rubella, CMV, HIV, and tissues toxoplasmosis, syphilis Medical and nursing procedures – hepatitis B,  These hairlike projections (up to several hundred per HIV, staphylococcal and pseudomonas infection cell) may be confined to one end of the organism (polar Zoonoses – cysticercosis, trichinella, brucellosis, pili) or distributed more evenly over the surface leptospirosis, hydatid disease, rabies, psittacosis Arthropods – malaria, dengue, typhus fever,  Examples: plague

Microbial Adherence 

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Once in or on the host, most microbes must anchor themselves to a tissue or tissue factor. Possible exceptions are organisms that directly enter the bloodstream and multiply there. [Harrison’s] Specific ligands or adhesins are found on the surface of the microbe which functions in attachment (anchoring and promoting cellular entry) and also eliciting host responses critical to the pathogenic process. [Harrison’s] o Adhesins are surface structures that

anchor the microorganism to tissue , promote cellular entry and elicit host responses 

HIV utilizes its envelope glycoprotein (gp) 120 to enter host cells by binding to both CD4 and one of two receptors for chemokines (designated CCR5 and CXCR4).

Microbes produce a lot of adhesins specific for multiple host receptors. Some microbes adsorb host proteins onto  their surface and utilize the natural host protein receptor

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Strains of Escherichia coli isolated from urinary tract infections express mannose-binding type 1 pili, whose binding to integral membrane glycoproteins called uroplakins that coat the cells in the bladder epithelium is inhibited by dmannose.

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Other strains produce the Pap (pyelonephritisassociated) or P pilus Jnfluenz that mediates binding to digalactose (gal-gal) residues on globosides of the human P blood groups.

Flagella are long appendages attached at either one or both ends of the bacterial cell (polar flagella) or Page 3 of 11

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distributed over the entire cell surface (peritrichous  flagella). The protein subunits form a tight helical structure and vary serologically with the species.  

Other bacterial structures involved in adherence to host tissues include specific staphylococcal and streptococcal proteins that bind to human extracellular matrix proteins such as fibrin, fibronectin, fibrinogen, laminin, and collagen. o

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Eukaryotic pathogens (amoebas, plasmodia) use surface glycoproteins (lectins) that bind to specific carbohydrates on the host’s cell surface. Examples:

Fibronectin appears to be a commonly used receptor for various pathogens; a particular amino acid sequence in fibronectin, Arg-Gly-Asp or RGD, is a critical target used by bacteria to bind to host tissues.

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Plasmodium vivax binds (via Duffy-binding protein) to the Duffy blood group carbohydrate antigen Fy on erythrocytes.

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Entamoeba histolytica expresses two proteins that bind to the disaccharide galactose/N-acetyl galactosamine. Leishmania uses glycoprotein (gp63) that promotes complement binding but not the lytic activity of the macrophages so it uses the complement system to gain entry to the macrophage. Schistosoma mansoni expresses carbohydrate epitope related to the Lewis X blood group antigen that promotes adherence of helminthic eggs to vascular endothelial cells under inflammatory conditions as part of hepatic granuloma formation

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Binding of a highly conserved Staphylococcus aureus surface protein, clumping factor A (ClfA), to fibrinogen has been implicated in many aspects of pathogenesis.

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The conserved outer-core portion of the Host Receptors lipopolysaccharide (LPS) of P. aeruginosa  Host molecules or ligands that microbial adhesions mediates binding to the cystic fibrosis bind to (for adherence) transmembrane conductance regulator (CFTR) o Sugars on airway epithelial cells—an event that o Ig superfamily appears to be critical for normal host resistance o Growth factors to infection.

A number of bacterial pathogens, including coagulasenegative staphylococci, S. aureus, and uropathogenic E. coli as well as Yersinia pestis, Y. pseudotuberculosis, Y. enterocolitica, Bordetella species, and Acinetobacter baumannii, express a surface polysaccharide composed of -1-6-linked-poly-N-acetyl-d-glucosamine. One of its functions is to promote binding to materials used in catheters and other types of implanted devices. 

Fungal Adhesins  Fungi express different proteins that adhere to the host’s fibronectin, laminin and collagen. Inhaled fungi are usually ingested first by alveolar macrophages in the lungs where they transform into pathogenic phenotypes.  Examples: o The product of the Candida albicans INT1 gene, Int1p, bears similarity to mammalian integrins that bind to extracellular matrix protein. o The agglutinin-like sequence (ALS) mediates the adherence of pathogenic Candida to host tissues. o B. dermatitidis produces WI-1 that mediates adherence to CD11b/CD18 integrins as well as to CD14 on macrophages.

Eukaryotic Pathogen Adhesins

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Integrins Extracellular matrix component Transport proteins Complement receptor

MICROBIAL GROWTH AFTER ENTRY Once established on the mucosal surface or skin site, pathogenic microbes must replicate before causing fullblown infection in the host. Viral particles release their nucleic acids within cells: o Positive-strand RNA – direct translation o Negative-strand RNA – transcribed to an mRNA o Retroviruses (reverse RNA) – transcribed to a complementary DNA o DNA (for DNA viruses) – direct transcription of mRNA o REMEMBER that viruses, inside the protein coat, have RNA or DNA which they release into the target cell. The released RNA or DNA must undergo, transcription (RNA – mRNA) and translation (mRNA to polypeptide chains or proteins) so that new viral products are made.

Bacteria must acquire specific nutrients or synthesize from precursors found in certain locations in the body (this may explain tropism or the preferential affectation of different parts of the body by pathogens) – pathogens have the ability to obtain nutrients for growth and survival from specific environments o H1 subtype influenza found on respiratory epithelium Page 4 of 11

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o o 

Neisseria Jnfluenza found on the urogenital epithelium Shigella spp. Found on the gastrointestinal epithelium

Temperature restrictions limit growth to specific tissues and influences many pathogens and growth

 usually relies on it o Rhinoviruses grows at 33°C and replicates in the cooler nasal tissue o Mycobacterium leprae grows at cooler body sites o Fungi choose cooler, exterior, keratinous layers

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Endospores form when environment changes orEncounters with Phagocytes Phagocytosis and Inflammation nutrients are exhausted, dormant but viable 

Microbial Biofilms    

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initiation of protective and non-pathogenic inflammatory response. If the epithelial cell barrier is broken (ulceration, trauma), uningested microorganisms can potentially enter the submucosa and cause infection (seen in Salmonella enterica serovar typhimurium causing typhoid fever) Low bacterial inocula epithelial cell ingestion and subclinical inflammation are efficient means to eliminate pathogens, while at higher inocula a proportion of surviving bacterial cells enter the host tissue through the damaged mucosal surface and multiply, producing disease

The reason why microbes keep on growing inspite of antibiotic treatment. This is common in Staphylococci, fungi, like candida  Matrix enclosed bacterial populations that adhere to a surface, interface, or each other Responsible for dental plaque, clogged water  pipes; form on synthetic medical implants However there are cases that biofilms may be created in the endocardium like in endocarditis and this is why endocarditis is quite difficult to  treat Leads to altered metabolism, production of extracellular virulence factors Decreased susceptibility to antibiotics by forming an exclusion barrier or directly complex with them

Phagocytosis of microbes is a major INNATE host defense that limits the growth and spread of pathogen that is why phagocytes appear rapidly at sites of infection in conjunction with the initiation of inflammation.

Activation of phagocytes is a key step in initiating inflammation and migration of additional phagocytes into affected sites Bacterial pathogens are ingested by Polymorphonuclear neutrophils (PMNs). Eosinophils are found on protozoan or multicellular parasitic sites of infection. Successful pathogens must avoid being cleared by professional phagocytes.

Microbial factors that in interact with phagocytes: o LPS of Gram (-) bacteria o Lipotechoic acid of Gram (+) bacteria

AVOIDANCE OF INNATE HOST DEFENSES [Harrison’s]: Multicellular hosts have a variety of innate surface defense mechanisms that can sense when pathogens are present and contribute to their elimination.  Skin is acidic and bathed in fatty acids toxic to many microbes  Mucosal surfaces are covered by a barrier composed of a thick mucous layer that entraps microbes and facilitates There will be an attachment of bacteria to the their transport out of the body by mechanisms such as receptors leading to the initiation of phagocytosis. mucociliary clearance, coughing and urination. Once inside there will be lysosomal activity and  Mucous secretions contain antibacterial factors such as microbial killing. A release of microbial products will lysozyme and antiviral factors like interferons. then follow which will lead to the activation of the  Gastric acidity is lethal to many pathogens ingested with inflammatory cascade. This is the reason why there food. can be and excessive inflammatory response.  Most mucosal surface (nasopharynx, vagina, GIT) have resident flora of commensal microbes that interfere with Avoidance of Phagocytosis the ability of pathogens to colonize and infect a host.  Release toxin that destroys phagocyte Encounters with Epithelial Cells [Harrison’s] Prevent opsonization by releasing protein  Many bacterial pathogens have been shown to enter  epithelial cells as a means for dissemination to adjacent  Prevent contact by capsule or deeper tissues or as a route to sanctuary to avoid  Inhibit fusion of phagoloysosome ingestion and killing by professional phagocytes.  Organism escapes into the cytoplasm and o Less virulent strains of many bacterial replicates within the phagocyte pathogens are more adept at entering epithelial  Resists killing by producing antioxidants, etc. cells than are more virulent strains  However, some studies proposed that epithelial cell entry may be primarily a manifestation of host defense, Evasion Strategies resulting in bacterial clearance by both shedding of STRATEGY EXAMPLE epithelial cells containing internalized bacteria and

Elicit minimal response

HSV latent stage

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Evade effects of response Depress host response Antigenic change Rapid replication Survive in weakly responsive persons

Mycobacteria in granulomas HIV destroys T cells Viruses (H1N1) spirochetes Virusse, bacteria, protozoa Genetic hetergenicity 

Decrease cytotoxic T cell recognition of infected cells (Epstein-Barr virus EBNA1 antigen and

cytomegalovirus IE protein) Produce virus-encoded complement receptor proteins that protect infected cells from complement-mediated lysis (herpesvirus and vaccine virus) Elaborate superantigen-like proteins (mouse mammary tumor virus and related retroviruses and the rabies nucleocapsid). Survival of Microbe in Host  Superantigens activate large populations of T cells that  Concealment of antigen express particular subsets of the T cell receptor protein, o Privileged sites (CNS, joints, testes, causing massive cytokine release and subsequent host reactions placenta, cysts, host DNA) o Mimicry (eg Streptococci and cardiacBacterial Toxins muscle)  Toxin elaborating bacteria o C. diphtheria (Diphtheria) o Antigen uptake o C. botulinum( Botulism)  Tolerance o C. tetani (tetanus) o Infection during embryonic life  Enterotoxin producing organisms o Production of large amounts of antigen o E. coli o Exploit gaps in immune repertoire o Salmonella o Upset balance between Ab and TH1 and o Shigella TH2 o Staphylococcus o Vibrio TISSUE INVASION AND TISSUE TROPISM [Harrison’s]  Toxin with syndrome production Tissue Invasion o Staph- TSS toxin 1 o Strep- erythrogenic toxin Some pathogens spread from the initial site to deeper tissues. o P. aeruginosa- exotoxin A, S, T, U o Bordetella- pertussin toxin  VIRUS can spread via the: o Nerves – rabies virus  Direct injection of toxin to host cells o Plasma – picornavirus o Salmonella o Inside migratory blood cells – poliovirus, o Yersinia Epstein-Barr virus o P. aeruginosa  BACTERIA may invade deeper layers by: Endotoxin o Intracellular uptake by epithelial cells  The lipid A portion of gram-negative LPS has potent biologic o Traversal of epithelial cell junctions activities: o Penetration through denuded epithelial surfaces o Sepsis, fever, muscle proteolysis, uncontrolled  FUNGAL PATHOGENS almost always take advantage of intravascular coagulation, shock. host immunocompromise to spread HEMATOGENOUSLY  Effects of lipid A are mediated by the production of potent to deeper tissues. cytokines due to LPS binding to CD14 and signal transduction via TLRs, particularly TLR4. Tissue Tropism Invasion  The propensity of certain microbes to cause disease by infecting specific tissues Many diseases are caused primarily by pathogens  Factors in the cell, route of viral entry, viral capacity to growing in tissue sites that are normally sterile. penetrate into cells, viral genetic elements that regulate gene expression, and pathways of viral spread in a tissue all affect tissue tropism  Disease that follows bacteremia and invasion of the  Examples: meninges by meningitis-producing bacteria appears to  HBV- liver cells be due solely to their ability to gain access to these o EBV- B lymphocytes tissues, multiply in them, and provoke cytokine o Polio- neurons production leading to tissue-damaging host o N. gono- genital tract inflammation. o N. mengitidis- oropharynx

TISSUE DAMAGE AND DISEASE Viral Disease 

Downregulate

MHC

molecule

production

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Melanism has been shown to protect the fungal cell against death caused by phagocyte factors such as nitric oxide, superoxide, and hypochlorite.

(adenovirus E3 protein)

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Make proteins that interfere with interferon (influenza virus and poxvirus) Page 6 of 11

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Morphogenic variation and production of proteases (e.g., Components of Host Response the Candida aspartyl proteinase) have been implicated in fungal invasion of host tissues.

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If pathogens are effectively to invade host tissues (particularly the blood), they must avoid the major host defenses represented by complement and phagocytic cells. o

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Bacteria most often avoid these defenses through their surface polysaccharides—either capsular polysaccharides or long O-side-chain antigens characteristic of the smooth LPS of  gram-negative bacteria.  Ability of some organisms to present the capsule as an apparent self-antigen through molecular mimicry.

Cellular immunity: through cytotoxic T cells Humoral immunity: through antibody production by B cells o Antibodies: recognize and bind to foreign antigens, impede function of organism, facilitate its removal o Complement: adhere and disrupt o Phagocytic cells: engulf, kill, and digest o

Host Response

Note: he simply enumerated the components of the B and T cells, refer to previous lecture if you can’t remember 

 Reticuloendothelial system: monocyte derived Outcome of infection depends on the balance phagocytic cells that clear circulating organisms in between an effective response that eliminates a the liver, spleen, kidney, LN, brain pathogen and an excessive inflammatory o However for patients with complications in response the liver, there can be more complications  Cytokine production: stimulate inflammatory leading to bacteremia response  Abscess or granuloma formation Macrophages  Local or systemic inflammation  Produced in bone marrow, tissues  Killing mechanism: oxidative, nitric oxide, Acute Inflammatory Response cytokines  Opsonization: engulfment by phagocytic cells Activated by IL-1, IL-6 and TNF-alpha, IFNγ, IL-4, facilitated by opsonins (C3B) GM-CSF, microbial products  Margination: PMNs align alongside blood vessel  Secretes lysozyme, cytokines, etc. wall  Chemotaxis: marginated PMNs attracted to siteNeutrophils of C3B coated bacteria  Produced in the bone marrow  Killing mechanism: oxidative and non-oxidative  Activated by TNF  Secretes lysozyme  Deficient states: CGD, myeloperoxidase, chemotactic, Chediak-Higashi 

T Helper (TH) Cells  TH1 subset: mediate chronic reactions (eg tuberculosis) When we talk of the acute inflammatory reaction you o IL-2, IFNγ will see that because of the trigger of the bacterial  TH2 subset: attachment of course the inflammatory cells will o IL-4, IL-5, IL-6 trigger a cascade of the compliment system. You will see here the complement mediators forming a complex leading to chemotaxis of various factors. These all lead to the inflammatory cascade.

inflammatory

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T-cell recognition leading to activated macrophages.  There is this microbial peptide that will be linked to the receptors of the T helper cells, that will later on lead to the activation of the inflammatory cascade where TNF will be released. The T-cell wall will trigger the killing of the parasites within the macrophages. Cytotoxic T Lymphocyte Carries out both antigen specific recognition and killing of target cell   Recognition is associated with Class I MHC  Killing mechanism: leakage due to insertion of perforin, DNA fragmentation, apoptosis Extracellular Killing  Natural killer cells: cytotoxic cells that attach to the surface of virally infected cells and release granules that enter cells through pores and lead to programmed cell death (apoptosis)  Eosinophils: important against helminthes; produce major basic protein (MBP), perforins, and O2 metabolites that damage the cells

Stimulate acute phase response Increase loss of mean body mass leading to anorexia Some populations will not produce fevers in the face of infection or be asymptomatic because of the lack of an immune response. This is especially seen in the elderly.

TRANSMISSION TO NEW HOSTS Most pathogens exit via the same route by which they entered: o Respiratory pathogens by aerosol from sneezing and coughing or through salivary spread o Gastrointestinal pathogens by fecal-oral spread o STDs by venereal spread o Vector-borne organisms by either direct contact with the vector through a blood meal or indirect contact with organisms shed into the environment.

Factors affecting transmission o Number of microorganisms shed (inoculum size) o Stability in the environment o Resistance to drying or thermal inactivation o Number of microorganisms required to infect a fresh host and site infection o Genetics o Activity of the host

SUMMARY: MICROBIAL PATHOGENICITY 

Cytokines  Inflammatory mediators released from the trigger of the TNF-alpha   Regulatory proteins produced by nucleated cells   Have autocrine and paracrine effects   Major fever-inducing cytokines: IL-1a, IL-1b, TNFa, INFa, IL-6  Inhibitory cytokines: IL-1ra, TGFb, IL-4, IL-10 o Prevents excessive immune response  Contribute to control of infection  Can contribute to development of pathology Effects of Cytokines   IL-1 and TNF o Mediate local phagocytic cell emigration and activation o Mediate release of lipid derived mediators  – Platelet activating factor – Prostaglandin – Thromboxane  IL-8: chemotaxis and release of enzymes by neutrophils   Vasodilation   Activation of T and B lymphocytes  Enhance killing by phagocytic cells

Make contact with appropriate surface o Certain organisms are usually tropic to certain areas of the body Reach unique niche on or within the host Overcome host defenses Multiply and secure its potential transmission to a new susceptible host o The biggest problems are of course the humans who become infected and become sources for the transmission of these diseases

FEBRILE RESPONSE A complex physiologic reaction to disease involving a cytokine-mediated rise in the core temperature, generation of acute phase reactants, activation of numerous physiologic, endocrinologic, and immunologic systems. Due to infection, malignancy, collagen vascular disease, etc.

PYROGENS Substances that cause fever Exogenous pyrogens: usually microorganism and toxins of microbial origin o Exotoxin Page 8 of 11

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Can also be drugs that we take; may not  Organism? necessarily be an organism  Effective drug? Endogenous pyrogens: derived from host cell Infection? Where? o Ag/Ab complexes with complement History o Steroid hormone metabolites  Presenting symptoms are frequently influenza-like o Bile acids  Pattern of illness – onset and duration of symptoms o Cytokines o

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ADVANTAGES OF FEVER  Impairs growth and virulence of certain bacteria Increases phagocytic and bactericidal activity of neutrophils Increases cytotoxicity of lymphocytes  Increases the ability to survive an infection Paracetamol is not usually given unless fever  elicits too much discomfort DISADVANTAGES OF FEVER

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Increases oxygen consumption Increases caloric and fluid requirements  Increased muscle catabolism leading to decreased body weight and negative nitrogen balance Decreased mental acuity leading to delirium and stupor; seizures in children Neural tube defects in fetuses

and about changes in severity or rate of progression over time Host factors and comorbid conditions – lack of splenic function, alcoholism with significant liver disease, IV drug use, HIV infection, diabetes, malignancy, organ transplantation, and chemotherapy all predispose to specific infections and frequently to increased severity. Factors in identifying nidus for invasive infection – recent URTI, influenza, or varicella; prior trauma; disruption of cutaneous barriers and the presence of foreign bodies Contact with pets or other animals, or activities that might result in tick or mosquito exposure Recent dietary intake, medication use, social or occupational contact with ill individuals, vaccination history, recent sexual contacts, and menstrual history

Travel Review of systems: focus on any neurologic signs or sensorium alterations, rashes or skin lesions, and focal pain or tenderness and should also include a general review of respiratory, gastrointestinal, or genitourinary symptoms

Physical Examination  Specific signs Unregulated rise in body temperature, in which  Combination of signs pyrogenic cytokines are not directly involved and Signs suggest site of infection against which standard antipyretics are ineffective Patient may appear either anxious and agitated or Failure of the thermoregulatory response lethargic and apathetic.

HYPERTHERMIA

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MANAGING INFECTIONS PROBLEMS TO SOLVE 

Fever

is usually present, except for elderly patients and compromised hosts [e.g., patients who are uremic or cirrhotic and those who are taking Meningitis or encephalitis glucocorticoids or nonsteroidal anti-inflammatory drugs Central (NSAIDs)] who may be afebrile despite serious Drug underlying infection Heat stroke Blood pressure, heart rate, and respiratory rate – determine the degree of hemodynamic and metabolic Malignant hyperthermia compromise Malignant neuroleptic syndrome  Airway must be evaluated to rule out the risk of obstruction from an invasive oropharyngeal infection HYPOTHERMIA  Etiologic diagnosis may become evident in a thorough Some patients may not present with fever but skin examination o Petechial rashes – meningococcemia or Rocky instead a lowering of temperature Mountain spotted fever Oral temperature less than 35oC or 95oF o Erythroderma – toxic shock syndrome (TSS) and o Hypoglycemia drug fever. o Hypothyroidism  Areas of erythema or duskiness, edema, and tenderness o Hypoadrenocorticism may indicate underlying necrotizing fasciitis, myositis, or o Overwhelming infection myonecrosis. o Intoxications  Careful assessment of mental status for signs of early encephalopathy. Evidence of nuchal rigidity or focal o Cold exposure neurologic findings should be sought.

Extreme Hyperthermia

Infection? Where?

Organism? 

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o Selection of drug regimen that will ensure More often, there are no clues compliance and effectiveness Investigations  Absence of major organ system side effects o Clinical samples → laboratory o Often times the patient present with symptoms that are too general to identify What is empiric antimicrobial usage? the actual etiologic agent. Laboratory  Use of antimicrobial proven effective based on findings are helpful in these cases for epidemiologic data on potential pathogens for a diagnosis. But test must be in accordance particular infection to the most probably location of the  Choice will depend on the following modifying infection factors: o Microorganisms: suspected etiologic DIAGNOSTIC APPROACH agent and patterns of local antimicrobial GOAL: determination of the etiologic cause susceptibility o Host Factors: age, pregnancy, Laboratory tests concomitant disease(s), host defense o Tempo and complexity of work-up depend mechanism, site of infection, and severity on: of infection – Diagnostic considerations o Drug factors and previous antibiotics, – Pace of illness etc. – Immune status  Appropriate specimens for Gram stain and culture Microbiologic examination and sensitivity should be taken prior to start of o Gram stain antibiotics o Culture and sensitivity

Other Important Laboratory Examinations What is directed antimicrobial therapy?  Imaging techniques  Use of antimicrobial for proven or identified o X-ray pathogens of the infection being treated o CT scan  Agents should be the most cost-effective and the o MRI least toxic with narrowest spectrum  Serologic tests (including ELISA) o Viral infections Irrational Use of Antibiotics  Antigen detection tests o Malaria  Favor selection of resistant microorganisms o S. influenza, H. influenza, N. meningitidis  Promote ineffective and wasteful utilization of o These are only true for those not living in antibiotics endemic areas  Polymerase chain reaction Choice of Antimicrobial Agents Again, we must be aggressive when we believe the patient is immunocompromised or presenting with severe manifestations of the disease. We must be familiar with how to give antibiotics properly.

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RATIONAL ANTIMICROBIAL USE Drug?

Nature and site of infection o Severity o Probable organism/etiologic agent(s) – Sensitivity pattern o Route of administration Host factors o Host defense o Co-morbid conditions o History of allergy Drug factors

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Empirical, initially Culture and sensitivity → specific  Quality of sputum sample: How do you know whether a sputum sample has good quality via Know Your Antibiotic microscopy?  Spectrum of activity o There should be 25  Adverse effects (patient tolerability) WBC/high power field  Cost (affordability, availability) o To differentiate contamination  Local clinical experience ANTIMICROBIAL THERAPY

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Rapid eradication of infecting organisms o Empiric coverage against the pathogens pending culture results

likely

COMBINATION ANTIBIOTIC THERAPY Page 10 of 11

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o Penicillin, cephalosporins Provide adequate coverage against mixed infections/multiple pathogens  Inhibition of some aspect of cell function o Intra-abdominal or brain abscess o Protein synthesis o Diabetics with microvascular disease – Aminoglycosides, tetracycline, chloramphenicol, macrolides Prevent resistance o DNA replication o Imipinem + AG for systemic – Rifampicin, quinolones Pseudomonas infection o Microbial enzymes Obtain synergism or additive activity – Sulfonamides, INH o Beta lactams + AG against enterococci, Bacterial S. viridans, and Pseudomonas resistance o Trimethoprim + sulfamethoxazole for Antibiotic Type Mode of action mechanism enteric Gram(-) Aminoglycosides Block protein Inactivation Lessen toxicity –not really done or practiced : gentamycin synthesis PARENTERAL TO ORAL SWITCH Beta-lactams: Usually occurs after 48 hours penicillins, >90% of patients have normal T and decreased cephalosporins WBC (1 to 6 days) Criteria Glycopeptides: o No clinical indication for continuing IVvancomycin therapy Macrolides o No abnormal GI absorption o Temperature returning to normal o Signs or symptoms related to infection: Quinolones improving or resolved o WBC and differential counts returning to normal Rifampin o C-reactive protein returning to normal

ANTIMICROBIAL RESISTANCE 

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Tetracyclines

Block cell wall formation Block cell wall formation Block protein synthesis

Inactivation, mutation

Mutation of binding molecules Ribosome protection

Inhibit DNA replication Inhibits bacterial RNA polymerase Block protein synthesis

Serious and ever increasing problem o Affects the clinical management of an infected patient Trimethoprim Block formation – May cause treatment failure sulfonamides of nucleic acids – Increased hospitalization, and f-met morbidity, and death Results to adverse consequences and costs TWO MAJOR MECHANISMS: ***END*** o Bacterial enzyme inactivates antibiotic References: PPT, Harrison’s 18th ed, o Alteration in the microbe itself trans

Mutation of binding molecules Mutation of binding molecules Inactivation Mutation of binding molecules

2012 and 2013

MULTIDRUG RESISTANCE

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Note: Sir said to review the spectrum of coverage of Treatment of infections due to these organismsthe different antibiotics (like which organisms they are remains difficult and expensive active against). It might come out in the exam.  Affects patient outcomes Steph o Enhanced virulence of the organisms o Limited options and delay in the administration of appropriate antibiotic

MECHANISM OF ACTION – ANTIBIOTICS 

Inhibition of cell wall synthesis

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Edited by: Jordan