An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease

Abstract

Streptococcus pneumoniae (Spn) colonizes the nasopharynx and can cause pneumonia. From the lungs it spreads to the bloodstream and causes organ damage. We characterized the in vivo Spn and mouse transcriptomes within the nasopharynx, lungs, blood, heart, and kidneys using three Spn strains. We identified Spn genes highly expressed at all anatomical sites and in an organ-specific manner; highly expressed genes were shown to have vital roles with knockout mutants. The in vivo bacterial transcriptome during colonization/disease was distinct from previously reported in vitro transcriptomes. Distinct Spn and host gene-expression profiles were observed during colonization and disease states, revealing specific genes/operons whereby Spn adapts to and influences host sites in vivo. We identified and experimentally verified host-defense pathways induced by Spn during invasive disease, including proinflammatory responses and the interferon response. These results shed light on the pathogenesis of Spn and identify therapeutic targets.

Streptococcus pneumoniae Binds to Host Lactate Dehydrogenase via PspA and PspC To Enhance Virulence

“…The vital role of these proteins in pneumococcal biology is highlighted by the fact that most clinical isolates of Spn carry both proteins (5,29,30), and mutants deficient in PspA and PspC are markedly reduced in virulence in a variety of experimental models (31)(32)(33)(34). PspA and PspC are among the most common and highly in vivo-expressed CBPs (5,14,29,35,36), and immunization with these proteins as antigens has been demonstrated to confer protection against invasive pneumococcal disease, especially when used in combination (31,37,38). Nonetheless, and despite .30 years of study on PspA and PspC, prior to this report, the role of the NPB in pneumococcal biology was undetermined.…”

Intranasal Vaccine Delivery Technology for Respiratory Tract Disease Application with a Special Emphasis on Pneumococcal Disease

“…In humans, pneumococcal carriage is believed to be a prerequisite of invasive disease [85,86], which occurs when immunity is compromised, as is observed in the elderly. The transition from benign colonizer to lethal pulmonary or systemic pathogen also involves changes in bacterial transcript profiles and morphology [83,[87][88][89]. This was highlighted in recent studies that showed that the set of genes expressed by pneumococci during colonization were distinct from those expressed during lung infection as well as during bacteremia, indicating that the bacteria adapt to their host in an infection site/organ-specific manner [83,87].…”

“…The transition from benign colonizer to lethal pulmonary or systemic pathogen also involves changes in bacterial transcript profiles and morphology [83,[87][88][89]. This was highlighted in recent studies that showed that the set of genes expressed by pneumococci during colonization were distinct from those expressed during lung infection as well as during bacteremia, indicating that the bacteria adapt to their host in an infection site/organ-specific manner [83,87]. Importantly, sets of conserved genes were upregulated across the several strains tested, suggesting they could be potential vaccine targets that induce strain-independent protection [87,89].…”

“…This was highlighted in recent studies that showed that the set of genes expressed by pneumococci during colonization were distinct from those expressed during lung infection as well as during bacteremia, indicating that the bacteria adapt to their host in an infection site/organ-specific manner [83,87]. Importantly, sets of conserved genes were upregulated across the several strains tested, suggesting they could be potential vaccine targets that induce strain-independent protection [87,89]. Similarly, it is well-established that regulation of capsule expression is required for bacterial virulence [90].…”

Neuraminidase B controls neuraminidase A-dependent mucus production and evasion

“…Even though the expression of nanA and nanB in vivo has been established, previous in vivo studies examining the contribution of Spn's neuraminidases have yielded mixed results, [9,29,35,[37][38][39]. The lack of a colonization defect for the ΔnanA,nanB::janus mutant was surprising considering its robust mucus adherence phenotype.…”