Host-Pathogen Interactions in Gram-Positive Bacterial Pneumonia

Abstract

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Despite broad literature including basic and translational scientific studies, many gaps in our understanding of host-pathogen interactions remain. In this review, pathogen virulence factors that drive lung infection and injury are discussed in relation to their associated host immune pathways. CAP epidemiology is considered, with a focus on Staphylococcus aureus and Streptococcus pneumoniae as primary pathogens. Bacterial factors involved in nasal colonization and subsequent virulence are illuminated. A particular emphasis is placed on bacterial pore-forming toxins, host cell death, and inflammasome activation. Identified host-pathogen interactions are then examined by linking pathogen factors to aberrant host response pathways in the context of acute lung injury in both primary and secondary infection. While much is known regarding bacterial virulence and host immune responses, CAP management is still limited to mostly supportive care. It is likely that improvements in therapy will be derived from combinatorial targeting of both pathogen virulence factors and host immunomodulation.

Keywords: inflammation; influenza; lung; staphylococcus; streptococcus; superinfection.

FIG 1

Pore-forming toxins and their receptors in pneumonia. Staphylococcus aureus and other bacterial toxins involved in bacterial pneumonia are shown. S. aureus alpha-toxin (Hla), Panton-Valentine leukocidin (PVL), leukotoxin AB (LukAB), and phenol-soluble modulins (PSMs) bind to their corresponding membrane receptors to mediate damage and inflammation. C5aR and C5L2, complement component 5a receptors; CD11b, subunit that forms the integrin α_Mβ₂, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3); ADAM10, disintegrin and metalloproteinase domain-containing protein 10; FPR2, formyl peptide receptor 2. PSMs and Hla can target both human and mouse cells, while PVL and LukAB are human-specific toxins. Streptococcus pneumoniae cytolysin pneumolysin (PLY) and Serratia marcescens toxin ShlA both bind to components of the membrane, i.e., cholesterol (Chol) or phosphatidylethanolamine (PE), respectively, to induce damage and inflammation.

FIG 2

Pore-forming toxins induce the NLRP3 inflammasome in phagocytes. Bacteria that encode pore-forming toxins can induce the NLRP3 inflammasome by forming pores within the membrane and facilitating potassium efflux. ATP, potentially leaving the cell via bacterial pores, binds to the purinoceptor P2X7 and induces K⁺ efflux that contributes to NLRP3 inflammasome activation and induces lysis in neutrophils through an unknown mechanism. Potassium efflux leads to oligomerization and activation of the NLRP3 inflammasome, consisting of the sensor protein NLRP3, adapter protein ASC, and pro-caspase-1, leading to cleavage and activation of effector caspase-1. Activation of caspase-1 leads to cleavage of pro-IL-1β and pro-IL-18 and subsequent release from the cell. Inflammasome activation can also lead execution of necrotic cell death via pyroptosis as well as DAMP release in neutrophils. Caspase-1 can also cleave components of the phagocyte NADPH oxidase, NOX2, which can lead to loss of endosomal acidification. Bacterial pores on the endosome also contribute to lack of acidification due to loss of membrane permeability as well as preventing the mitochondria from localizing with the endosome due to the strong activation of NLRP3. Loss of acidification leads to increased survival of bacteria within the phagosome/endosome. Cathepsin B (CTSB) can be released from damaged lysosomes and can also induce NLRP3 inflammasome activation, via an unknown mechanism. The antioxidant resveratrol can inhibit the expression and activation of the NLRP3 inflammasome, leading to a decrease in bacterial survival.

FIG 3

Preceding influenza inhibits pulmonary immunity to bacterial pneumonia. Pulmonary innate immunity to bacteria (left) is orchestrated mainly by epithelial cells, macrophages, neutrophils, and gamma-delta T cells. The epithelium provides a physical barrier to infection and expresses antimicrobial peptides to kill extracellular bacteria. This expression is augmented by type 17 cytokines from gamma-delta T cells (γδT). Alveolar macrophages (AMs) patrolling the airspaces engulf bacteria through phagocytosis, eventually leading to killing in acidified phagosomes. Bacterial pore-forming toxins (notably Staphylococcus aureus Hla and Streptococcus pneumoniae PLY) allow the entry of bacterial DNA into the cytoplasm of alveolar macrophages, leading to interferon beta (IFN-β) production via STAT1/2 signaling. This IFN-β can bind receptors on epithelial cells but also signals in an autocrine fashion on these macrophages to induce production of RANTES and other chemokines. These chemokines recruit mainly neutrophils from the bloodstream, which can also phagocytose bacteria. Both neutrophils and macrophages contain the NLRP3 inflammasome, a scaffold of proteins serving to activate caspase-1 and other enzymes that cleave IL-1 cytokine family members (mainly IL-1β). Finally, macrophages prevent excess inflammation by engulfing dead or dying cells through a phagocytic process known as efferocytosis. Influenza induces susceptibility to bacterial infection through inhibiting antibacterial immune defenses (right). Influenza virus preferentially infects epithelial cells, leading to destruction of the epithelial barrier from viral infection and later cytotoxic CD8⁺ T cell activation. This increases the ability of bacteria to adhere to the epithelium. Production of both type I (α and β) and III (λ) IFNs is highly increased during the antiviral immune response, leading to inhibition of type 17 cytokines and antimicrobial peptide production. IL-1β production is also reduced by preceding influenza. Overall, chemokine production is reduced, while airspace cellularity is increased due to the immunopathologic neutrophil recruitment in response to influenza virus infection. Phagocytosis of bacteria by both macrophages and neutrophils is blunted, concomitant with a decrease in intracellular reactive oxygen species important for bacterial killing in the phagosome.