Inflammasome/IL-1β Responses to Streptococcal Pathogens

Abstract

Inflammation mediated by the inflammasome and the cytokine IL-1β are some of the earliest and most important alarms to infection. These pathways are responsive to the virulence factors that pathogens use to subvert immune processes, and thus are typically activated only by microbes with potential to cause severe disease. Among the most serious human infections are those caused by the pathogenic streptococci, in part because these species numerous strategies for immune evasion. Since the virulence factor armament of each pathogen is unique, the role of IL-1β and the pathways leading to its activation varies for each infection. This review summarizes the role of IL-1β during infections caused by streptococcal pathogens, with emphasis on emergent mechanisms and concepts countering paradigms determined for other organisms.

Keywords: IL-1β; Streptococcus; caspase-1; inflammasome; pyroptosis.

Figure 1

Major effector mechanisms of the inflammasome. A cell containing active inflammasomes releases several inflammatory signals to other cells, including prostaglandins/eicosanoids, IL-1β, and IL-18. The other major cell process activated is programed cell death by pyroptosis, whereupon the released cellular contents can be detected by a number of pattern-recognition receptors to further inflammatory signaling. Pyroptotic cell death also releases any intracellular pathogens, exposing them to direct killing by complement or antimicrobial peptides or phagocytosis by neighboring cells.

Figure 2

Inflammasome activation by the streptococci. Two primary NLRs form inflammasomes during streptococcal infections, NLRP3 and AIM2. NLRP3 detects membrane disruption by the pore-forming toxins encoded by all the major streptococcal species. These pores also allow bacterial DNA in to the cytosol for detection by AIM2. Either NLR can form an inflammasome scaffold for the activation of caspase-1, the primary protease responsible for the hydrolysis of IL-1β into its mature form.

Figure 3

IL-1β/inflammasome licensing pathways. IL-1 and the NLR proteins responsive to the streptococci require induction. Cell–cell signaling can provide this priming signal in the form of IL-1β or TNF-α. More commonly during bacterial infection, bacterial factors detected as pathogen-associated molecular patterns by TLRs provide this signal. TLR2 detects bacterial lipoproteins and is broadly sensitive to Gram-positive pathogens. TLR4 is able to detect the pore-forming toxins of several species of streptococci. When the streptococci are intracellular and the phagosome is disrupted, several additional receptors are involved. TLRs 7, 8, 9, and 13 detect bacterial nucleic acids, while NOD1 and NOD2 detect bacterial cell wall fragments.