Protection from the acquisition of Staphylococcus aureus nasal carriage by cross-reactive antibody to a pneumococcal dehydrogenase

Abstract

Nasal colonization by Staphylococcus aureus is the major risk factor for disease and transmission. Epidemiological studies have reported a reduced risk of S. aureus carriage in immunocompetent but not in immunocompromised children colonized by Streptococcus pneumoniae. We investigate the hypothesis that the immune response to pneumococcal colonization affects S. aureus colonization. We demonstrate that pneumococcal colonization in mice inhibits subsequent S. aureus acquisition in an antibody-dependent manner and elicits antibody that cross-reacts with S. aureus. We identify the staphylococcal target of cross-reactive antibody as 1-pyrroline-5-carboxylate dehydrogenase (P5CDH), and the homologous immunogen in S. pneumoniae as SP_1119, both of which are conserved dehydrogenases. These antigens are necessary and sufficient to inhibit the acquisition of S. aureus colonization in a mouse model. Our findings demonstrate that immune-mediated cross-reactivity between S. pneumoniae and S. aureus protects against S. aureus nasal acquisition and thus reveal a paradigm for identifying protective antigens against S. aureus.pneumococcus | methicillin-resistant S. aureus | vaccine T he Gram-positive bacterial pathogen Staphylococcus aureus is responsible for significant morbidity, mortality, and excess healthcare costs worldwide. The management of S. aureus disease has become increasingly difficult because of the rising prevalence of methicillin-resistant S. aureus (MRSA), which can account for 60% of S. aureus infections in hospital and community settings (1, 2). Given the limited treatment options for MRSA infection, novel preventative approaches are needed to protect against S. aureus infection and transmission.A predominant risk factor for S. aureus infection and transmission is asymptomatic colonization of the anterior nares (3). Eighty percent of S. aureus invasive infections in humans are caused by the host's colonizing strain (4). However, the specific host and bacterial determinants of S. aureus nasal carriage are not well understood (5). In children, significantly reduced S. aureus colonization rates have been associated with carriage of another member of the upper respiratory tract flora, Streptococcus pneumoniae (6-14). These large and geographically diverse cohorts have demonstrated reproducibly that colonization with S. pneumoniae reduces the risk of S. aureus carriage by approximately half. This interference phenomenon has been reported for both vaccine and nonvaccine serotypes of S. pneumoniae (13). Moreover, pneumococcal vaccination, which reduces S. pneumoniae carriage, has been associated with an increased incidence of S. aureusinduced otitis media in children (15).The etiology of this interference phenomenon between S. pneumoniae and S. aureus colonization is unknown. Although in vitro studies have demonstrated that hydrogen peroxide secreted by S. pneumoniae is bactericidal to S. aureus in coculture (16-18), neither hydrogen peroxide secretion by S. pneumoniae nor hydrogen peroxide sensitivity of S. aureus...

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion of Trypanosoma cruzi

“…In Cryptococcus neoformans, a pathogenic yeast, PUT2 is required for the optimal production of major cryptococcal virulence factors, and in mice, infection with a ⌬PUT2 mutant was determined to be nonvirulent (96). Another study has shown that the immune response underlying pneumococcal colonization affects Staphylococcus aureus colonization and identified S. aureus P5CDH as a target in a cross-reactive antibody response (97). In trypanosomatids, the participation of enzymes with pivotal roles beyond their canonical metabolic functions has been reported.…”

Staphylococcus aureusandStreptococcus pneumoniaeinteraction and response to pneumococcal vaccination: Myth or reality?

“…While the HIV studies may suggest that T-cell immune response plays a role in the interference, Lijek et al demonstrated in an in vivo murine model that S. pneumoniae colonization inhibits subsequent S. aureus acquisition in an antibody-dependent manner, via cross-reactive antibodies targeting conserved dehydrogenases, 1-pyroline-5-carboxylate dehydrogenase (P5CDH) of S. aureus and a putative S. pneumoniae dehydrogenase: SP_1119. 66 Yet, these antibodies have not been found in humans. In addition, other studies did not find correlations between levels of particular S. aureus or S. pneumoniae antibodies and rates of S. aureus colonization.…”

Impact of Staphylococcus aureus on Pathogenesis in Polymicrobial Infections

“…Therefore, direct antagonism mediated by H 2 O 2 is an unlikely reason for their antagonism. Rather, the antibody response generated during S. pneumoniae infection, although ineffective in restricting this pathogen itself, is effective in providing cross-protection against S. aureus (71,72).…”