Immunity to extracellular and intracellular bacteria

Introduction

Immune response plays a vital role in protecting against infectious agents. It is the main impediment against the occurrence of disseminated infections that are usually associated with a high death rate. It is a well-known fact that for virtually all infectious diseases, the number of individuals exposed to infection is much higher than those actually presenting with a disease. This indicates that most persons are able to destroy these microorganisms and thus prevent the progression of an infection. By contrast immune deficiencies, whether of innate immunity (phagocytic cell dysfunction or complement deficiency) or adaptive immunity (antibody production deficiency or T-cell function deficiency), are strongly associated with increased susceptibility to infections.

 Immune response against bacteria

Bacteria are the microorganisms that most frequently cause infections in humans. The natural barriers against infection agents as well as innate and adaptive immunity participate in the protection mechanism against bacteria.

Ø  Via complement-mediated lysis

When bacteria, such as Neisseria meningitidis, invade the body, they are attacked by immune proteins called complement proteins. Complement proteins assist in bacterial killing via three pathways, the classical complement pathway, the alternative complement pathway or the lectin pathway. The first steps of the classical complement pathway require the binding of antibodies to the surface of the target bacterium. The antibodies then become targets for one particular complement protein complex, known as C1 – C1 binds to the tail (known as Fc region) of the antibody. Once bound, C1 initiates a cascade of cleavage and reforming of complement complexes that ends in the binding of several complement proteins to the surface of the bacterium in the form of a membrane attack complex (MAC) (Figure 1), or can generate opsonins that label a bacterium for destruction. MAC can insert into the cell membrane of Gram-negative, but not Gram-positive, bacteria. There, it produces pores that allow the entry of membrane damaging molecules, such as lysozyme, and makes the bacterium susceptible to osmotic lysis. The alternative complement pathway does not require antibody to initiate the lysis of bacteria. In this pathway, complement proteins from a complex known as C3 directly bind to bacteria and activate downstream components in the complement cascade, once again ending in formation of MAC that causes lysis of the bacterium. During the lectin pathway, mannan-binding lectin (MBL) binds to proteins containing mannose residues that are found in some types of bacteria (such as Salmonella spp.). Once bound, MBL forms a complex with an enzyme called MBL-activated serine protease (MASP). In this form, this enzyme activates C3 convertase (by cleaving C2 and C4 complement components) that participates in forming MAC.

Ø  Via phagocytosis

Bacteria may also be killed by phagocytes. Immune proteins like acute phase proteins (like complement) and antibodies bind to the surface of bacteria by a process called opsonisation. Opsonised bacteria are, therefore, coated with molecules that phagocytic cells recognise and respond to. Activated phagocytes engulf and destroy opsonised bacteria by a process called phagocytosis. Complement C3b is a particularly important opsonisation protein for controlling bacterial infections by this mechanism. Opsonisation allows killing of Gram-positive bacteria (e.g. Staphylococcus spp.) that are resistant to killing by MAC.After bacteria are ingested by phagocytosis (Figure 2), they are killed by various processes that occur inside the cell, and broken into small fragments by enzymes. Phagocytes present the fragments on their surface via class II major histocompatibility (MHC class II) molecules.

Circulating helper T cells recognise these bacterial fragments and begin to produce proteins called cytokines. Two major groups of helper T cells are known as Th1 and Th2 cells. These cell types differ in the types of cytokine they secrete. Th1 cells predominantly produce interferon-g (IFN-g), which promotes cell-mediated immune mechanisms (see below). Th2 cells produce mostly interleukin-4 (IL-4), which promotes humoral immunity by activating B cells. B cells make antibodies that stick to extracellular bacteria and prevent their growth and survival.

Ø  Via cell-mediated immunity

Some bacteria engulfed during phagocytosis avoid the killing mechanisms of the phagocyte to survive inside cells. Macrophages are a common targets for intracellular bacteria (e.g. Salmonella spp.) that live inside cell compartments. These bacteria cannot be detected by complement or antibody but, instead, are eliminated using a cell-mediated response. Infected macrophages present bacterial peptides on their cell surface using MHC class II molecules. This mechanism is called antigen presentation. A helper T cell surveys MHC class II molecules with its T-cell receptor (TCR) to observe the peptides they hold. If a bacterial peptide is presented, the Th1 cell releases IFN-g. This cytokine stimulates killing mechanisms, (such as production of lysozyme) inside the infected macrophage to digest and destroy the invading bacterium. IFN-g also increases antigen presentation by cells, making the bacterium more visible to the immune system and more prone to attack.

Immune response against intracellular bacteria

Some intracellular bacteria like pathogenic or facultative are able to multiply within the phagocytes, so their elimination from the patients requires modified strategies.

Ø  Innate immunity to intracellular bacteria

Phagocytes and natural killer cells provide innate immunity to the intracellular bacteria. However some bacteria survive and multiply easily in the phagocytes, the phagocytes need to be stimulated by the secretions of these bacteria in order to clear the infection. The secretions from these bacteria are recognized by TLRs and cytoplasmic proteins of the NOD-like receptor (NLR) family so that they stimulate the phagocytes to degrade the invading bacteria. In addition to the intracellular bacteria, activated natural killer cells produce IFN-γ, which consecutively stimulates macrophages and cytokines. Although innate immunity provides protection from most of the bacteria but some intracellular bacteria like Listeria monocytogenes need cell mediated immunity in order to be eliminated from the body.

Ø  Adaptive immunity to intracellular bacteria

T cell-mediated immunity plays a significant role in providing protection against intracellular bacteria. CD4+ T-cells and CD8+ cytotoxic T lymphocytes are the two major forms of cell mediated immunity that participate in phagocytosis or killing of infected cells, respectively. Both the, CD4+ T-cells and CD8+ cytotoxic T lymphocytes work together to provide protection against the intracellular bacteria. Granulomatous Joint initiative of IITs and IISc – Funded by MHRD inflammation acts as a marker for most of the infections due to intracellular bacteria, which occurs because of T-cell and macrophage stimulation. Macrophage stimulation that occurs as an antigenic response towards intracellular microbes is sometimes able to cause tissue damage. The response shown by different patients towards the intracellular microbes decides the development of the disease and its consequence. One neat example of such type of response is shown by leprosy patients. Leprosy is a disorder caused by Mycobacterium leprae and it exists in two forms, the lepromatous and tuberculoid form. Lepromatous form is characterized by feeble cell-mediated immune response and high specific antibody titer while the tuberculoid form shows low specific antibody titer but very strong cell-mediated immune response. Although the reasons attributed to this type of response are still speculated and not yet verified, one of the factors that are given significance is regarding varied pattern of cytokine production and T-cell differentiation in patients.

Ø  Dodging of immune system by intracellular bacteria

Intracellular bacteria tend to dodge the immune system in many ways comprising evading into the cytosol or preventing phagolysosome fusion and by overpowering the reactive oxygen species by their microbicidal activity. These bacteria have the potential to cause chronic infections because they can survive the phagocyte mediated elimination and thrive for years in the body and may show reversion of the disease.

Immune response against extracellular bacteria

 Extracellular bacteria are those that multiply and reside outside the host cell. These bacteria mainly affect the cells in two ways. They either attack by causing inflammation and tissue damage or by producing toxins.

Ø  Innate immunity to extracellular bacteria

Innate immunity to extracellular bacteria essentially involves three processes.

·         Stimulation of phagocytes- Phagocytes takes the help of surface receptors and Fc receptors to identify extracellular bacteria and its opsonization with the help of antibodies, respectively. Most of these receptors are associated with promotion of phagocytic activity and microbicidal activity.

·          Induction of inflammatory response- Antigen presenting cells like dendritic cells in addition to phagocytes are stimulated by microbes and these cells secrete cytokines which are responsible for causing leukocyte infiltration at the site of inflammation.

·         Activation of complement system- Both gram positive and gram negative bacteria stimulate alternative pathway of complement system and mannose expressing bacteria stimulate lectin pathway of complement system by binding to mannose binding lectin.

Ø  Adaptive immunity to extracellular bacteria

The immunity that plays major role against extracellular bacteria is the humoral or antibody mediated immunity as it prevents the infection by neutralizing the toxins. Usually polysaccharide antigens are prototypic thymus-independent antigens and humoral immunity is the basic line of defense against polysaccharide-rich encapsulated bacteria. The antibodies in such cases defend the body by neutralization, opsonization, phagocytosis and stimulation of complement system. Extracellular bacteria also stimulate the production of CD4+ helper T cells which induces inflammation and phagocytic activity. Besides this, these antigens may cause some mutational disorders and also the affected individual may have reduced immune response towards microbial infections.

Ø  Immune evasion by extracellular bacteria

1.      Polysaccharide antigens or encapsulated bacteria are more lethal as compared to a strain devoid of capsule because they resist phagocytosis.

2.      Capsulated bacteria inhibit alternate pathway of complement system due to the presence of sialic acid.

3.      One more way of evading immune response by extracellular bacteria is due to the genetic edition of surface antigens. E.g. surface antigen of some specific bacteria is contained in their pili. Pili contain a protein antigen called “pilin” and this pilin undergoes gene variation. Pili are the structures of bacteria responsible for bacterial adhesion to host cells.

Conclusion

Bacterial pathogens are often associated with many health issues globally and are capable to cause diseases irrespective of host species involved. Although there are principal protective immune response mechanisms associated like HMI, CMI and many more which are capable of defending our system from these harmful invaders.