2. INTRODUCTION
• From the moment of birth, the host is constantly exposed to a wide
variety of bacteria and viruses
• The host manages to either eliminate or ward off these invading
organisms, and a symbiosis is achieved between microbes and the
host.
• There are two major pathways to achieve this resistance: nonspecific
and adaptive
3. NONSPECIFIC RESISTANCE
• Nonspecific or natural resistance refers to barriers, secretions, and
normal flora that make up our external defences.
• Phagocytes and complement are also involved
• The Skin, mucosal lining of mouth and respiratory tract are excellent
defence mechanism
• Invading organisms trigger an inflammatory cascade, which stimulates
these cells to adhere to vascular epithelium and actively migrate
toward the infection
4. NONSPECIFIC RESISTANCE
• The macrophages reside in the subepithelial tissues of the skin and
intestine and line the alveoli of the lungs
• Microbes that penetrate an epithelial surface will encounter local
tissue macrophages called histocyte
• If the organism enters via blood or lymph, then defence is provided by
fixed macrophages called Kupffer cells
• Once engaged with the organism, these macrophages release a
number of macrophage-derived cytokines, which nonspecifically
amplify the immunological and inflammatory reactions to the
invading microbe.
6. Infectious microbe recognition
• Infectious microbes display certain molecular patterns that are
necessary for microbial virulence
• Many of these molecular patterns such as lipopolysaccharide in the
outer membranes of gram-negative bacteria seem to be particularly
potent activators of mammalian cells
• The mammalian receptors responsible for recognition of PAMPs are
called pattern recognition receptors
• The failure of the immune system to recognize a pathogen’s PAMP
could lead to a delay or blunting of the immune response, resulting in
unchecked invasion by the microbe.
7. ADAPTIVE IMMUNITY
• A specific immune response to invading microbes is conveniently
divided into humoral and cellular immunity.
• The importance of each arm of the specific response varies from
infection to infection
• Individuals with antibody deficiencies are particularly prone to
repeated infections with pyrogenic bacteria
• These individuals can mount a normal response to most viruses
8. ADAPTIVE IMMUNITY
• After activation of the TLRs, the DCs are transformed into more mature
cells with a high expression of MHC
• The DCs then migrate to the lymph nodes to activate antigen-specific naïve
T cells
• The production of IL-12 drives these cells to TH1 cells, which produce
interferon-δ,
• Whereas IL-4 drives them toward TH2 cells producing IL-4, IL-5, Il-10, and
IL-13
• These latter cytokines are of interest as they are also responsible for the
development of allergic diseases
9. BACTERIAL INFECTION
• Immune responce may respond to soluble products of the cell such as
toxins or released structural antigens like LPS of a given gram-
negative bacterial cell.
• Most bacterial antigens are T-cell dependent and require helper T
cells for initiation of the immune response.
• Some bacterial antigens such as endotoxins can be powerful
stimulators of the immune response and lead to polyclonal activation
of B lymphocytes.
10. BACTERIAL EVASION OF IMMUNE DEFENSE
• Capsules play an important role for long-term survival of pathogens
• Antigenic variation is another mechanism whereby bacteria evade the
immune system.
• N. gonorrhea, N. meningitidis, Haemophilus influenza, and others that
secrete proteases that hydrolyze IgA antibody
• Some strains of staphylococci secrete catalase, which prevents them from
being killed inside phagocytic cells
• M. tuberculosis, which can lie dormant for years inside a granulomatous,
caseous lesion called the Ghon complex.
• Finally, a number of organisms display antigens on their surface that are
cross-reactive with human antigens
11. VIRAL INFECTIONS
• In general, viral infections are self-limited and usually produce long
term immunity, and secondary attacks by the same virus are
uncommon
Of the large number of herpes viruses, only eight infect humans,
• Two general features of pathogens of these viruses are important.
• First, there must be close contact between infected and noninfected
individuals for transmission to occur and no intermediate host is
involved
• Second, after the primary infection, herpes virus will persist in the
host for life
12. FUNGAL INFECTION
• Fungi cause many diseases, most of which are adequately handled by
the immune system of the normal host
• However, the increased use of immunosuppressive drugs – the
immunosuppression secondary to HIV infection – has raised our
awareness of these infections
• For example, Candida albicans
• Another organism that is receiving wide attention is the fungus
Pneumocystis carinii (now called Pneumocystis jiroveci)
• Systemic infections in the immunocompromised host have a higher
mortality rate
13. PARASITIC INFECTION
• Protozoa are a diverse group of parasites, but malaria, and
trypanosomiasis globally account for most of the problems
encountered in parasitic diseases
• The balance between host and parasite is twofold:
- The parasite may be too virulent for the host or may evade the
immune surveillance and thus kills the host.
- Conversely, the immune response may be vigorous and kill the
parasite, thereby jeopardizing its survival.
• Thus, the survival of any parasite depends on a balance between
induction of immunity and escape from surveillance.
Mechanical barriers are highly effective, and the skin (our largest organ) is highly suited to this protection
Yet, a defect in the mucosal lining of the respiratory tract, which occurs in cystic fibrosis, results in a heightened susceptibility to many infections.
Phagocytosis is promoted by opsonins (usually IgG antibody) and complement.
Similarly fixed macrophages called Langerhans cells are also present in the epidermis of the skin
Kupffer cells, which line the sinusoids of the liver
Most pathogenic microorganisms have evolved methods of resisting phagocytosis.
Another approach (taken by both group A streptococci and staphylococci) is the release of potent extracellular toxins, which kill phagocytes with the formation of pus.
An intriguing bacterium, Mycobacterium tuberculosis, can be ingested by phagocytes but resists intracellular killing, often persisting for years in the macrophage
toll-like receptors (TLR) quickly evolved as a crucial system for alerting the host to the presence of numerous infectious agents
Perhaps the best example of an incomplete recognition by the TLR system is a gram-negative bacterial infection in the C3H/HeJ mouse.
As few as two colonyforming units of Salmonella typhimurium can kill this mouse.
Further exploration of this extraordinary virulence revealed that the mouse harbored a point mutation (P712H) in the TLR4, which results in defective signal transduction in response to LPS and a heightened susceptibility to gram-negative infections.
The family of TLRs is a highly specialized system that can identify a number of microbial and endogenous ligands and activate the immune system to respond
certain components of the immune response are crucial for controlling a particular infection
Yet the absence of mucosal antibody does make them susceptible to some enteroviruses
Although it is clear that innate immunity is the first line of defence against invading organisms, the TLRs are also playing a role in adaptive immunity, and the dendritic cell (DC) appears to be playing a key role in linking the innate and adaptive immune responses
with the appearance of invading organisms, DCs recognize these pathogens through their TLRs. Fortunately, they express the full repertoire of TLRs
allergic disease and atopy has markedly increased in the industrialized countries compared with developing countries over the past decades, and one hypothesis is that this increase is linked to the reduction of bacterial infections, which occurs in a cleaner environment, a hypothesis known as the “hygiene hypothesis”
the molecular basis for this recognition is not known for a single ligand.
Furthermore, the characterization of TLR-dependent signalling for the instruction of adaptive immune responses has just started to be explored.
Because TLRs play such a crucial role in innate and adaptive immune responses to distinct virulence factors, the development of selective inhibitors/activators may be a worthwhile endeavor to help manage a number of infectious and immunologic diseases.
Yet certain cell antigens, such as the pneumococcal polysaccharides, are T-cell independent.
They are large-molecular-weight molecules, and in children, antibody response to these antigens may take four to six years.
Thus, younger children are susceptible to these infections.
This rise in immunoglobulin levels is believed to be nonspecific since only a small portion of the total immunoglobulin level is directed to the endotoxin.
There are several ways in which bacteria can survive in the host by evasion of the immune defenses
The M protein (the most important virulence factor of the group A streptococcus) has been shown to exhibit antigen variation in the environment, and new M protein molecules appear regularly in human isolates of group A streptococci
crossreactive with human antigens. This could result in an enhanced immune response to host tissue antigens or a diminished response secondary to similarities between bacterial and self-antigens.
To eliminate virions from entering noninfected cells and to eliminate virus infected cells, two major pathways of the immune response are initiated.
The humoral response is primarily directed against virions, while the T-cell response is primarily directed against infected cells.
The humoral response may directly neutralize the virus, but complement dependent enhancement of viral phagocytosis or complement lysis of virus also may occur.
For example, Candida albicans can cause superficial infections in the normal host and is found throughout the intestinal tract and commonly in the vagina.
The organism is usually kept under control by the bacterial flora, but changes in these flora secondary to overuse of antibiotics or changes in hormone balance will favor a chronic superficial infection. All of this is exacerbated in the immunocompromised host
Pneumocystis jiroveci ; which has a commensal relationship with the lung in the normal host.
However, the sudden onset of pneumonia with this organism secondary to HIV infection in a child or adult is often the first sign of an underlying suppressed immune system caused by HIV
This category includes Histoplasma capsulatum (pulmonary infection), Coccidiodes immitis (acute pneumonitis), and Cryptococcus neoformas (meningitis, lung lesions).
Such systemic infections may occur in normal individuals, and the cell-mediated immune response is the more important factor in control or prevention of them.
However, all of these fungal infections (superficial and systemic) are more likely to occur in immunosuppressed individuals, especially those in which the cell-mediated immune response is compromised.
As with viruses, there is a third possible outcome.
If the fungal infection is not eliminated or causes persistent infection, then the host response may trigger a hypersensitivity reaction.
As an example, Aspergillus fumigatus infections
Malaria
The worldwide incidence of malaria is estimated at 300 million–500 million people, and at least 1 million die each year of the disease, mostly of cerebral malaria and usually young children.
Cerebral malaria is usually associated with infection with Plasmodium falciparum and not Plasmodium vivax. Patients react to protozoal infection with activation of macrophages and monocytes with the release of cytokines TNF, IL-1, and IL-6
Although most protozoa stimulate the production of IgG and IgM antibodies, these antibodies are probably not protective, and thus vaccines have not yet been successful in the control or prevention of malaria.
In summary, protozoa have developed a wide variety of techniques to evade the immune system.
This makes it extremely difficult both to eliminate these protozoa and to produce vaccines that are effective against them.
Thus, the field is wide open to new and innovative approaches to eliminate this class of organisms
