Pneumococcal surface protein A (PspA) and pneumococcal
surface protein C (PspC, also called CbpA) are major
virulence factors of Streptococcus pneumoniae (Spn). These surface-exposed
choline-
binding proteins (CBPs) function independently to inhibit opsonization, neutralize antimicrobial factors, or serve as adhesins. PspA and PspC both carry a
proline-rich domain (PRD) whose role, other than serving as a flexible connector between the N-terminal and C-terminal domains, was up to this point unknown. Herein, we demonstrate that PspA binds to
lactate dehydrogenase (LDH) released from dying host cells during
infection. Using recombinant versions of PspA and isogenic mutants lacking PspA or specific domains of PspA, this property was mapped to a conserved 22-amino-acid nonproline block (
NPB) found within the PRD of most PspAs and PspCs. The
NPB of PspA had specific affinity for
LDH-A, which converts
pyruvate to
lactate. In a mouse model of
pneumonia, preincubation of Spn carrying
NPB-bearing PspA with
LDH-A resulted in increased bacterial titers in the lungs. In contrast, incubation of Spn carrying a version of PspA lacking the
NPB with
LDH-A or incubation of wild-type Spn with enzymatically inactive
LDH-A did not enhance virulence. Preincubation of
NPB-bearing Spn with
lactate alone enhanced virulence in a
pneumonia model, indicating exogenous
lactate production by Spn-bound
LDH-A had an important role in pneumococcal pathogenesis. Our observations show that lung LDH, released during the
infection, is an important binding target for Spn via PspA/PspC and that pneumococci utilize
LDH-A derived
lactate for their benefit in vivoIMPORTANCEStreptococcus pneumoniae (Spn) is the leading cause of community-acquired
pneumonia. PspA and PspC are among its most important
virulence factors, and these
surface proteins carry the
proline-rich domain (PRD), whose role was unknown until now. Herein, we show that a conserved 22-amino-acid nonproline block (
NPB) found within most versions of the PRD binds to host-derived
lactate dehydrogenase A (
LDH-A), a metabolic
enzyme which converts
pyruvate to
lactate. PspA-mediated binding of
LDH-A increased Spn titers in the lungs and this required
LDH-A enzymatic activity. Enhanced virulence was also observed when Spn was preincubated with
lactate, suggesting
LDH-A-derived
lactate is a vital food source. Our findings define a role for the
NPB of the PRD and show that Spn co-opts host
enzymes for its benefit. They advance our understanding of pneumococcal pathogenesis and have key implications on the susceptibility of individuals with preexisting airway damage that results in
LDH-A release.