Bacteria can directly secrete protein toxins (exotoxins) and effectors that damage and/or allow invasion of host cells. In doing so, they aid virulence by allowing injuring host tissue and harming (e.g. by killing macrophages) or deflecting the immune system (e.g by a super-antigen response), which can help infection to spread. Protein toxins are broadly divided into cytolysins and intracellular enzymatic toxins that act on different aspects of bacteria: the cell membrane and intracellular targets. While bacterial effectors can have different purposes from bacterial adhesion to host cell apoptosis they must be injected by bacterial ‘needles’. Clinically, protein toxins and effectors have been exploited for treatments, such as in the tetanus vaccine where denaturing produces non-toxic immunogenic forms of the toxin for vaccination.

Cytolysins

Cytolysins disrupt host cell membranes and act by degrading membrane phospholipids or by inducing pore formation. This leads to cell lysis, although at a lower concentration can subvert host cell signal transduction, leading to release of leukotrienes and histamine as well as apoptosis. In doing so, they can disable immune cells and increase tissue damage to promote bacterial spread. Examples include the Clostridium perfringens alpha-toxin, a secreted phospholipase that degrades phospholipids to disrupt the host cell membrane. On the other hand, Streptococcus pneumonia secretes pneumolysin (a pore-forming toxin) to destroy host cells to avoidance of phagocytosis by alveolar macrophages and cause lung damage (which may destroy ciliated epithelium and prevent). Another pore-forming cytolysin is the hexameric VacA toxin secreted by H. pylori which destroy epithelial cells to form peptic ulcers. By inserting into the membrane, the VacA forms anion-selective channels that are endocytosed, disturbing the ion balance of late endosomes which fill up with water forming vacuoles.

Enzymatic toxins

Also known as A-B toxins, they bind to intracellularly active components. They enter the cell by receptor-mediated endocytosis and/or retrograde transport. In some cases, they are a single polypeptide that is cleaved into active fragments (diphtheria) while in other cases, they are multimeric (anthrax). Common targets of these enzymatic toxins can range from DNA (cleaved by cytolethal distending toxins from typhoid and E. coli) to transcription (Shiga toxin, a glycosidase that depurinases rRNA of the ribosome) factors and other intracellular proteins. Nevertheless, enzymatic toxins can also target specific cell types, including the tetanus toxin (TeNT). The TeNT B chain binds to a peripheral nerve membrane receptor, resulting in internalisation of the A chain, which undergoes retrograde transport to the CNS. It enters interneurons where it cleaves synaptobrevin (a V-SNARE protein required for vesicle fusion), therefore blocking inhibitory neurotransmitter release and resulting in uncontrollable muscle contraction and spastic paralysis.

Bacterial effectors

Effectors are similar to enzymatic toxins by acting intracellularly to subvert host function, but simultaneously different as they must be injected by bacterial ‘needles’. One example is Salmonella which utilises the “trigger mechanism” to enter host cells. By injecting effectors via a bacterial ‘needle’, the bacteria subvert the cytoskeletal rearrangement of the host cell allowing for internalisation similar to phagocytosis. The effectors mimicking eukaryotic cell proteins to induce acting binding and polymerisation (SipA or SipC) or signalling pathways (SptP). The genes encoding effectors (and needle) are on a pathogenicity island (SPI-1). Such cytoskeletal subversion is also utilised by enteropathogenic and enterohaemorrhagic E. coli (EPEC and EHEC)which inject effector proteins into the host cell, including a Tir (receptor) which turns around and binds the bacterial surface intimin resulting in subversion of host cell signal transduction and promotion of actin polymerisation to form a “pedestal” formation that tightly adheres the bacterium to epithelial cells. Of course, effectors can also drive other outcomes such as apoptosis in cells: Yersinia does this by injecting YopT, a GTPase protease that disrupts the cytoskeleton, and YopP, an acetyltransferase that inhibits signalling.