Pathophysiology of infection
1. Definitions
- Infection: (low Latin infectio, -onis , from inficere : to impregnate)
- Infection: penetration and development in a living being of microorganisms
- Microorganisms can cause lesions:
- by multiplying and
- possibly by secreting toxins
- or by spreading through the blood.
- Infection = proliferation of a pathogenic microorganism within a responsible host organism:
- of troubles or
- of malfunctions.
- Infection can be:
- Local
- Loco-regional
- General
- Focal (infectious focus is the origin of distant lesions).
- Infection can be specific (tuberculosis, syphilis, HIV) or caused by common germs.
2. World of infectious agents:
Infectious agents are:
1 – Bacteria (eubacteria, mycobacteria, protozoobacteria, etc.)
2 – Viruses (Coronavirus, Herpes virus, paramyxovirus, papillomavirus, etc.;)
3 – Parasites
4 – Mushrooms and yeasts
5 – Prions = unconventional transmissible agents (UNTA): no nucleic acid.
- Free living: the organism can provide for its own metabolic needs.
- Saprophytism: the organism feeds on organic or plant matter decomposing in the external environment.
- Commensalism: the organism feeds on organic matter from a living being (oral environment, intestine) without causing problems or spoliation in its host.
- Commensal flora or microbiota = set of these commensal species.
- Symbiosis: beings live in close collaboration in an association beneficial to both parties (balance of intestinal, oral or vaginal flora).
- Parasitism: the parasitic organism lives at the expense of a host which provides it with a biotope and/or nutrients necessary for its survival, this host suffering more or less seriously.
What is a tank 1?
This is the natural environment of the infectious agent.
It can be:
• Environmental: quite rarely
– soil (fungi, parasites, spore-forming bacteria such as Clostridium tetani )
– water ( Vibrio cholerae )
– air (Aspergillus spp.)
What is a tank 2?
• Animal: zoonoses
– Man = accidental host 🡪 highly pathogenic (eg Covid-19, SARS, avian flu) emerging diseases
– Man = frequent host (eg: rickettsioses, sleeping sickness, brucellosis, etc.) diseases in the process of disappearing
• Human: most frequent case (eg: cold, meningococcal meningitis, tuberculosis, AIDS, malaria, etc.)
– endogenous infections: the patient is his own reservoir.
Pathophysiology of infection
3. Bacterial infection
3.1. General:
- Bacteria: primitive cells; no compartmentalization separates the nuclear material (nucleoid) and the cytoplasm: these organisms are prokaryotes (without nuclei), capable of multiplying in an inert environment.
- Two types of bacterial infections
🡪 Community infections = Any infection occurring in a patient in their natural environment, their “community”.
🡪 Healthcare-associated infections (HAIs) = Any infection occurring during or following the care (diagnostic – therapeutic – preventive) of a patient if it was neither present nor incubating at the start of the care.
In IAS we find nosocomial infections (infection acquired in a health facility (neither incubating nor present on admission to the establishment) and infections contracted during ILS care (infection acquired during care provided outside a health facility).
- Commensal bacteria should be distinguished from saprophytic bacteria , which are therefore environmental bacteria. Their presence within a human organism is most often transient (a very brief passage phenomenon) except during destabilization of the microbiota , particularly during antibiotic therapy: the human organism can become colonized by saprophytic bacteria which have a tendency towards multi-resistance to antibiotics.
3.2. Pathogenic effect of bacteria
- There may be a conflict between the human body and the bacteria.
- Bacterial species capable of inducing infection have a pathogenic power whose mechanism is called pathogenicity.
– Pathogenic bacteria versus virulent bacteria.
🡪 “pathogenic” (qualitative notion) = being capable of inducing a disease.
🡪 “virulent” (quantitative concept): bacteria that will cause a simple fever when there is an extremely high inoculum; versus a very low inoculum which is lethal in 100% of cases.
- Different types of pathogenic bacteria:
3.2.1. The strict pathogen = its presence in the organism OBLIGATORILY indicates AN INFECTION because it never has a commensal relationship with the human organism. Ex: Mycobacterium tuberculosis (tuberculosis), Shigella (Shigellosis*: severe diarrhea).
3.2.2. Occasional pathogen = a transient carrier bacterium or commensal flora, which occasionally causes an infection, most often due to a contributing factor.
Ex: the pneumococcus germ responsible for pneumonia (in the oropharyngeal flora; 🡨🡪 pneumonia following a viral infection).
- Staphylococcus aureus infection = Staphylococcus aureus after a skin break. Present in the commensal flora of individuals (anterior nasal cavity). 1/3 of individuals are permanent healthy carriers; 1/3 are transient healthy carriers; 1/3 never carry it.
These potentially pathogenic bacteria are normally present in an individual outside of any infectious process = “healthy carrier individual”.
3.2.3. The opportunistic pathogen : bacteria that are only pathogenic in individuals whose defenses are profoundly and lastingly impaired (+++ severely immunocompromised individuals encountered in the hospital environment). These opportunistic pathogens may belong to the commensal flora or be saprophytes.
Ex: Staphylococcus epidermidis : we all have it on our skin. It is a “cousin” of S. aureus , devoid of the latter’s pathogenicity factors.
Normally: there is NEVER an infection with S. epidermidis. Its pathogenicity can develop in weakened subjects in hospital: it has an extraordinary ability to stick to synthetic material such as prostheses, catheters, etc.
– Pseudomonas aeruginosa in intubated patients in intensive care 🡪 pneumonia.
– Listeria monocytogenes 🡪 Listeriosis: normally never causes infection except in pregnancy. Infection especially in the fetus 🡪 possibly premature death.
3.3. Main mechanisms involved in the development of an infection and pathogenicity factors
There are 3 successive stages:
A. The need to come into close contact with the host = adherence.
B. A phenomenon of aggression (the infection itself) with a phenomenon of invasion by the bacteria within the human organism.
C. Then, the bacteria must persist: to do this, it has developed factors that allow it to escape the defenses of the human body.
NB: There are certain bacteria that bypass the first 2 steps: they do not need to invade because they use a vector (= a system that allows the microorganism to penetrate directly into humans.)
2 bacteria that use vectors:
– the tick for Lyme disease
– the flea for the plague.
- Establishing close contact with the host: “adherence”
- mobility of certain bacteria thanks to flagella, for example to cross mucus in order to come into contact with epithelial cells: Helicobacter pylori (responsible for ulcers)
- adhesion: bacteria have adhesins = structures that will specifically recognize receptors on the surface of eukaryotic cells and attach to them 🡪 explains that for certain bacteria, we have specificities of the infected site.
– Adhesin on fimbriae or pili (a fine structure (looks like a hair) at the end of which the adhesin is present) with possible retraction to adhere more intimately
– Simple adhesin, in the external membrane for example
Ex: Group A streptococcus (tonsillitis) uses an adhesin called M protein to adhere to the tonsils.
Once the bacteria has adhered:
- Need to feed to survive and possibly multiply 🡨🡪 War between the bacteria and the host for iron which is essential for humans but also for the bacteria.
– However, iron is never free (ALWAYS bound to proteins: transport proteins like transferrin, or reserve proteins like ferritin).
– Bacteria have developed amazing systems to capture iron: they excrete molecules called siderophores that will rip the iron from transferrin or ferritin, then be captured and internalized by the bacteria. These siderophores are essential for a bacteria to be pathogenic!!
B. “Attacking” the host and possibly entering it: “invasion phenomenon”
Aggression mechanisms can be of 3 types
• elements at the level of the bacterial wall: will cause an inflammatory reaction
• a secretion of enzymes by the bacteria: have deleterious effects on the tissues, without affecting the cells (simply what is pericellular)
• protein toxins (cytotoxins or exotoxins): are secreted and have a deleterious effect on the eukaryotic cells themselves.
B1. Elements of the bacterial wall
- There are conserved molecules at the bacterial wall. In particular, on GRAM bacteria, there is lipopolysaccharide (LPS) (at the external membrane), consisting of polysaccharide and lipid A.
- These elements can be recognized by receptors present on the host’s innate immunity cells: Toll Like Receptors (TLR).
- These receptors act as a monitoring system which will allow foreign bacteria to be detected and the defense systems to be triggered: inflammatory reaction, recruitment of phagocytic cells, etc.
- Problem: In some cases, the monitoring system is overwhelmed with an exaggerated reaction leading to shock with multiple organ failure
Especially for Gram-negative bacteria: lipid A can be responsible for this exaggerated reaction: it is the “endotoxin shock”. (Lipid “A” has a toxin function, and the toxin being a constituent of the membrane, we speak of “endotoxin”, different from exotoxins which are secreted and which go outside).
B2. Secretion of enzymes:
Enzymes capable of altering tissues or defense elements EXCEPT cells, promoting the dissemination of bacteria:
- proteases = hydrolysis of defensins (= antibacterial peptides)
- collagenases or hyaluronidases = enzymes capable of destroying the surrounding tissue of cells (collagen, hyaluronic acid, etc.) so that bacteria can progress and multiply.
- mainly found in pyogenic bacteria (S. aureus , group A streptococcus).
B3. Protein toxins (cytotoxins, exotoxins)
- Secreted by the bacteria, and action at a distance: alter the functions of eukaryotic cells.
- Can be responsible for all the pathogenicity of the bacteria on their own!! If we remove ONE gene (coding for the toxin) from the bacteria 🡨🡪 there is no more pathogenicity.
C. Evading host defenses:
Different structures allowing this:
🡪 The capsule is generally of the polysaccharide type:
– which has the capacity to protect the bacteria from defense systems (Antibodies [ATC] and complements) 🡪 high capacity of the bacteria to disseminate at the level of the organism and in particular at the level of the blood.
– Some very special capsules also have:
* an ability to inhibit complement activation
* saccharides which are also Anti self genes!! (Are present at the level of eukaryotic cells) 🡨🡪 we cannot make ATC with respect to these capsules!!
Some antigenic structures exposed to antibodies show great variability: Ex: The M protein of group A streptococcus has more than 70 variants 🡪 Anti-M antibodies are protective but in theory a human can have up to 70 tonsillitis in his life (if he encounters the 70 different serotypes)!!
Living hidden within the enemy, entering the cell and trying to survive there to be completely protected, without having too massive a deleterious effect:
– There are bacteria that have intracellular survival capabilities (in epithelial cells or even phagocytic cells).
We distinguish:
– obligate intracellular pathogens : have developed this intracellular survival system so much that they can only survive in the presence of cells (🡨🡪 concerns regarding antibiotic therapy because the antibiotic must first enter the cell and then the bacteria.)
– facultative intracellular pathogens : capable of surviving in or outside the cell.
Authentic mechanism of protection and long-term persistence in the body : Mycobacterium tuberculosis.
Pathophysiology of infection
4. Viral infection
- Virus: an isolated, akaryotic nucleic acid (DNA or RNA), without cellular structure 🡪 strictly intracellular multiplication.
4.1. The role of the environment : Viruses have a very hypothetical origin. The environment contains viruses that contaminate.
Virus “reservoirs”: rodents (Lassa virus 🡪 Fatal hemorrhagic fever), birds (West Nile virus: bird 🡪 mosquito 🡪 man), chimpanzee (HIV1).
4.2. Genetic background : We are not all the same within the population: some are sick, others are not.
4.3. Immune status. Three examples:
a. Anticancer chemotherapy: Neutrophils will see their function altered, there is neutropenia 🡪 risk of developing:
◦ Herpes Simplex Virus mucositis,
◦ respiratory infections with RSV (Respiratory Syncytial Virus) which cause bronchiolitis.
b. Organ transplantation (CD8): a patient who is going to receive a kidney transplant has his CD8 functions immunosuppressed so that he does not reject the graft.
c. HIV (CD4): decreased expression of CD4 T lymphocytes.
- Organ transplantation and HIV carry a risk of virus-induced cancer:
* Epstein Barr virus (EBV): B lymphoma
* Human Herpes Virus 8 ( HHV-8): Kaposi’s sarcoma
* Papillomavirus: carcinomas (of the anus, vulva, cervix).
Pathophysiology of infection
4.4. Acute viral infections:
Example: Hepatitis B virus
Transmission:
• intravenously, particularly in drug addiction
• by sexual intercourse
• mother-to-child transmission: if the mother is replicating the virus at a high level, there will be a lot of viral DNA and a lot of a protein which is a witness to replication called the HBe antigen : transmission is then 90%.
In contrast, if replication markers are absent, transmission is only 10%.
There are 8 AH genotypes.
4.4.1 – Evolution of serological markers during hepatitis B virus infection
This is a virus. You can see the partially double-stranded DNA, the capsid (HBcAg) and the envelope (HbsAg, s for surface).
The Hbc capsid antigen is not released into the bloodstream. However, anti-HBc antibodies are present. For anti-HBc Abs there are two dotted curves: one collapses at S36, these are anti-HBc IgMs. The other persists beyond this, these are anti-HBc IgGs.
SO :
– Three markers of hepatitis B virus replication:
➔ Viral DNA
➔ HBs antigen: surface antigen.
➔ HBe antigen
– Markers of the antibody response:
➔ Anti-HBc IgM antibodies: HBc is the capsid antigen
➔ anti-HBc IgG antibodies
➔ anti-HBe antibodies
➔ Anti-HBs antibodies
4.4.2 – Pathophysiology of hepatitis B:
In the case of viral hepatitis B, it is the immune conflict that creates the pathology.
TCD8 lymphocytes encounter infected hepatocytes which will create the disease.
Two types of cells:
– CD8 T lymphocytes (CTL)
– regulatory T cells (immunosuppressive functions)
➔ 1st case : acute hepatitis B
Hepatocytes are infected. CD8s come, destroy infected hepatocytes. Acute hepatitis = immunological conflict CD8 T – infected B hepatocytes
➔ 2nd case : Chronic carrier
There is an infiltrate of CD8 T lymphocytes and also an infiltrate of regulatory T lymphocytes.
Regulatory T cells repress TCD8 🡪 so the cellular immune response no longer exists.
Viruses replicate but hepatocytes are not destroyed because there is no immunological conflict.
➔ 3rd case : Fulminant hepatitis:
The number of TCD8 lymphocytes affecting hepatocytes is enormous.
CD8 are found to be directed against both infected and uninfected hepatocytes.
🡪 In 95% of cases: there are as many infected B hepatocytes as CD8 cells = acute hepatitis.
🡪 In 5% of cases: there are fewer CD8s than infected hepatocytes = chronic carrier.
🡪 There are more CD8 than infected hepatocytes = fulminant hepatitis.
🡨🡪 This is an immunological conflict between CD8 and hepatocytes.
4.5 – Persistent viral infections: Two examples:
4.5.1. Chronic infection:
4.5.1.1. Hepatitis C: the cell produces microRNAs that degrade viral RNAs. BUT the viruses replicate and mutate.
- After a certain time: small cellular RNAs can no longer degrade viral RNAs.🡪 conflict 🡪 inflammatory lesions 🡪 hepatitis.
- Then the immune system gets rid of the mutants.
4.5.1.2. HIV infection:
- In 94% of cases, when there is HIV infection, the viral load evolves, the immune system reacts and the TCD4 lymphocytes collapse 🡨🡪 Antiretroviral treatment.
- In 5% of cases, infected subjects are not treated but progress very slowly towards AIDS: these are the long term nonprogressors (LTNP) or the Elite Controllers (EC). There would be a beneficial role of certain types of HLA (B57, B27, B14).
- In 1/10000 cases, there is no retrovirus infection because the subject is delta CCR5 negative.
4.5.2. Latent infection: Herpes virus infections: Primary infection → viral load → clinical signs → latency phase → viral load → clinical signs.
– This time we are interested in micro RNAs which are produced by viruses (and not by the cell).
– A virus will replicate itself, produce micro RNAs which prevent its replication, the virus then remains hidden and reappears years later.
Virus infection → virus goes dormant → virus reactivates years later.
Example :
• chickenpox: replication → production of mi-RNA → 50 or 60 years later it causes shingles.
• infectious mononucleosis (in adolescents, due to the EBV virus, kissing disease): replication → clinical signs → production of microRNA → and later B lymphoma.
Pathophysiology of infection
4.6. The immune response to infection:
4.6.1 – Recognition of the viral agent by the cell:
When attacked by a virus, the cell must recognize this viral agent. It sees the aggressor through Toll receptors or cytoplasmic proteins.
➔ Toll receptors: These are the first elements that were identified as capable of identifying the aggressor.
These Toll receptors are located at the level of cell membranes, that is to say the cytoplasmic membrane but also the membranes of lysosomes and endosomes.
At the cytoplasmic membrane level: Toll 2 and Toll 4 recognize virus envelopes.
At the level of endosomes and lysosomes: Toll 3, Toll 7, Toll 8 and Toll 9 recognize single-stranded or double-stranded RNA and DNA.
➔ Cytoplasmic proteins:
There are also cytoplasmic proteins that can recognize the infection.
4.6.2 – Interferon alpha:
When there is an attack by a virus → the cells recognize the aggressor via Toll receptors → all the cells synthesize an antiviral molecule: interferon alpha ( INFα) .
There are two types of dendritic cells, both of which derive from CD34+ hematopoietic progenitors:
➔ Myeloid dendritic cells: mCD, present in peripheral tissues, blood and marrow.
➔ Plasmacytoid dendritic cells: pCD present in the lymph nodes , blood, marrow and thymus.
Dendritic cells play a fundamental role at two levels:
➔ The synthesis of INFα: pCD+++mCD+
➔ Antigen presentation: mCD+++pCD+
5. Concept of treatment:
Treatment of infection:
- bacterial uses antibiotics such as beta-lactams, tetracyclines, etc.
- Viral: preventive = vaccination. Curative = antivirals such as acyclovir, valaciclovir, etc.
- Mycoses: antifungals such as amphotericin B, ketoconazole, etc.
Pathophysiology of infection
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