The difference between intracellular and extracellular infections

Infections can manifest themselves through intracellular and extracellular bacteria.

Extracellular bacteria do not invade cells. Instead they proliferate in the extracellular environment which is enriched with body fluids. For example, P. aeruginosa is a non-invasive extracellular infection, that rapidly spreads to various tissues extracellular bacteria do not have the capacity to survive the intracellular environment or to induce their own uptake by most host cells. Intracellular bacteria invade host cells when it gives them selective advantage. Bacteria that can enter, survive and proliferate within eukaryotic cells are shielded from humoral antibodies and can be eliminated only by a cellular immune response. However, these bacteria must possess specialized mechanisms to protect them from the harsh environment of the lysosomal enzymes encountered within the cells. An example of this are small colony variants (SCVs) of S. aureus.

Extracellular infection

P. aeruginosa has several important virulence factors that serve different purposes. Including adhesion, siderophores, elastase, exo-toxins,  and coordinating. The interaction between P. aeruginosa type IV pili and the Asialo-GM1 mediates bacterial adherence to the epithelial cells. Typically, many pathogens  have a mechanism to steal iron from the host cell, as iron is often a limiting nutrient. For pseudomonas, the main molecule for transport is the peptide pyoverdin which is an ion chelator. It is excreted into the medium in its iron free form. The iron-bound form is recognised by ferric-pyoverdin recognition (Fpv) receptors (FpvA/FpvB) which release and internalise the iron from pyoverdine in a TonB-dependent mechanism. Elastase is a major virulence factor in P. aeruginosa , as it is believed it causes extensive tissue damage during infection in the human host. Elastase cleaves the connective tissue, IgA and IgG. Other immune-regulatory factors include the loss of flagellar synthesis, as the flagellin which makes up the flagella is an immunostimulant. P. aeruginosa has several independently regulated systems that produce toxins, including type-3-secretion system (T3SS), pyocyanin and cyanide synthesis. The T3SS acts like a molecular needle that injects toxins into the cytoplasm of the target organism. Most T3SS exo-toxins affect eukaryotic signalling pathways and thus interfere with a range of function in target cell physiology, e.g. arranging and maintaining the cytoskeleton. Pyocyanin disturbs the redox balance. P. aeruginosa can produce cyanide, which disrupts ATP generation via oxidative phosphorylation by blocking complex IV. In Pseudomonas, production of pyocyanin and proteases like elastase in quorum sensing (QS)-controlled, pyoverdin and cyanide is part-controlled, as is the T3SS. Different QS systems exist and have complex interactions.

Intracellular infection

SVCs They are auxotrophic for menadione, haemin or thymidine and have phenotypic traits making them well adapted for intercellular survival. S. aureus express microbial surface components recognising adhesive matrix molecules (MSCRAMMs) to adhere to host cells. MSCRAMMs are used to bind directly to the host cell surface membrane or to ligands such as fibronectin. Uptake is the attachment to the host cell which causes changes in the host cell cytoskeleton leading to forced phagocytosis in non-professional phagocytes. An interaction with integrin is the start point for S. aureus entering epithelial cells. Due to integrin-mediated signal transduction, integrin-linked kinase (ILK) activates leading to the reorganization of the actin cytoskeleton. S. aureus needs ILK activation to infiltrate epithelial cells. SCVs invade non-professional phagocytes more because of an increased expression of MSCRAMMs. SCVs cause host cell damage as they decreased production of alpha hemolysin and toxic shock syndrome toxin 1 (TSST-1). Alpha hemolysin is a pore forming toxin transcribed by the hla gene that can lead to the lysis of cells. TSST-1 is a toxin that activates the immune system leading to host immune cell-mediated cytotoxicity. Decreased production of such toxins allows the infected cell to survive for longer to accommodate the bacteria. SVCs have shown immune system resistance as they can resist lysosome bactericides better than normal colony variants. They also have reduced membrane potential that protects them from cationic proteins. SCVs also have increased polysaccharide intercellular adhesin which allows resistance to neutrophil’s non-oxidative defense mechanisms. Therefore, SCVs resist cytoplasmic defensive allowing them to survive for extended periods of time. Intracellular infections proliferate in the cells they invade as opposed to outside the cell. SCVs noticeably proliferate more than normal phenotype colonies.