Pneumococcal pneumonia: mechanisms of infection and resolution

Abstract

Vaccination and antimicrobial therapy remain the cornerstones of the management of pneumococcal pneumonia. Despite significant successes, the capacity of the pneumococcus to evolve in the face of the selective pressure of anticapsular immunity challenges immunization programs. Treatment focuses on antimicrobial therapy but ignores the central role of the dysregulated inflammatory response during pneumonia. Future therapeutic approaches need to build on the considerable recent advances in our understanding of the pathogenesis of pneumococcal pneumonia, including those from models of pneumonia. Enhancement of the essential components of the host response that prevents most colonized individuals from developing pneumonia and strategies to limit inappropriate inflammatory responses to lower respiratory tract infection are approaches that could be exploited to improve disease outcome. This review highlights recent discoveries relating to the microbial and host determinants of microbial clearance and regulation of the inflammatory response, which provide clues as to how this could be achieved in the future.

Figure 1.

Pneumococcal virulence factors influencing colonization and invasion. CSTs and ISTs of Spn show distinct characteristics, which are in part defined by polysaccharide capsule. CSTs are more readily coated with COMP, but ADHs, including pneumococcal surface protein A, choline-binding protein A, and PsrP, are more accessible in ISTs. In the URT, the CSTs are likely to colonize in part because when nonopsonized they are less susceptible to PMN. In contrast, CSTs are readily phagocytosed by AMs in the LRT and are less likely to cause invasive disease. ISTs less readily colonize the URT and are more likely to adhere to ECs and penetrate tissue, ultimately reaching BVs and establishing bacteremia. ISTs are also more resistant to phagocytosis by AMs. Independent of the capsule, PsrP will favor biofilm formation and resistance to AM phagocytosis, whereas production of pili and PsrP will enable attachment to epithelia. Pili and PLY will also influence invasion and amplification of the inflammatory response. ADH = adhesin; AM = alveolar macrophage; BV = blood vessel; COMP = complement; CST = colonizing serotype; EC = epithelial cell; IST = invasive serotype; LRT = lower respiratory tract; PLY = pneumolysin; PMN = phagocytosis by neutrophils; PsrP = pneumococcal serine-rich repeat protein; Spn = Streptococcus pneumoniae; URT = upper respiratory tract

Figure 2.

Pattern-recognition receptors involved in the recognition of Spn. A variety of Spn-derived factors can stimulate TLRs expressed both on the cell surface and on phagolysosome membranes. TLR2 recognizes LPs, TLR4 PLY and TLR9 unmethylated CpG dinucleotides in bacterial DNA. The release of factors can be aided by digestion of bacterial components by lysosomal enzymes. In addition, some digested fragments may be released from a pPL and engage cytosolic pattern-recognition receptors such as MDP, which engages Nod2. PLY also activates the NALP3 INF containing the ASC adaptor protein, and potentially other inflammasomes, although the mechanism of release of these factors from the phagolysosme awaits clarification and it is not clear if the release is selective or part of a more generalized permeabilization event. Bacterial DNA (Spn DNA) released from the phagolysosme is recognized by DAI in the cytoplasm. ASC = apoptosis-associated speck-like protein containing a caspase recruitment domain; DAI = DNA-dependent activator of interferon regulatory factors; INF = inflammasome; LP = lipopeptide; MDP = muramyl dipeptide; NALP3 = nucleotide-binding oligomerization domain-like receptor; Nod = nucleotide-binding oligomerization domain; Nod2 = nucleotide-binding oligomerization domain-containing protein 2; pPL = permeabilized phagolysosome; TLR = toll-like receptor. See Figure 1 legend for expansion of other abbreviations.

Figure 3.

Critical elements in the host response to Spn. AMs can phagocytose Spn, and ingested bacteria are killed within phagolysosomes and by apoptosis-associated killing. When the capacity of AMs to clear Spn is overwhelmed, AMs cooperate with EC through the release of IL-1 and other cytokines to stimulate the release of CXC chemokines, which leads to PMN recruitment to clear bacteria. The cell network also involves T cells and iNKT that aid bacterial clearance and can also regulate the neutrophilic inflammatory response.^, Th17 T cells aid neutrophil recruitment in particular in the upper airway via release of IL-17A. iNKT = invariant natural killer T cell. See Figure 1 legend for expansion of other abbreviations.