Adaptation to acid stress is an important factor in the transmission of intestinal microbes. The enterobacterium Escherichia coli uses a range of physiological, metabolic, and proton-consuming acid resistance mechanisms in order to survive acid stresses as low as pH 2.0. The physiological adaptations include membrane modifications and outer membrane porins to reduce proton influx and periplasmic and cytoplasmic chaperones to manage the effects of acid damage. The metabolic acid resistance systems couple proton efflux to energy generation via select components of the electron transport chain, including cytochrome bo oxidase, NADH dehydrogenase I, NADH dehydrogenase II, and succinate dehydrogenase. Under anaerobic conditions the formate hydrogen lyase complex catalyzes conversion of cytoplasmic protons to hydrogen gas. Finally, each major proton-consuming acid resistance system has a pyridoxal-5'-phosphate-dependent amino acid decarboxylase that catalyzes proton-dependent decarboxylation of a substrate amino acid to product and CO2, and an inner membrane antiporter that exchanges external substrate for internal product.

Plasmodium vivax shows a strict host tropism for reticulocytes. We identify transferrin receptor 1 (TfR1) as the receptor for P. vivax reticulocyte-binding protein 2b (PvRBP2b). The structure of the N-terminal domain of PvRBP2b involved in red blood cell binding was determined, elucidating the molecular basis for TfR1 recognition. TfR1 was validated as the biological target of PvRBP2b engagement by TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of P. vivax, but not to invasion of P. falciparum. Using Brazilian and Thai clinical isolates, we show that PvRBP2b monoclonal antibodies that inhibit reticulocyte binding also block P. vivax entry into reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of reticulocytes during P. vivax invasion.

The Escherichia coli inducible lysine decarboxylase, LdcI/ CadA, together with the inner-membrane lysine-cadaverine antiporter, CadB, provide cells with protection against mild acidic conditions (pHB5). To gain a better understanding of the molecular processes underlying the acid stress response, the X-ray crystal structure of LdcI was determined. The structure revealed that the protein is an oligomer of five dimers that associate to form a decamer. Surprisingly, LdcI was found to co-crystallize with the stringent response effector molecule ppGpp, also known as the alarmone, with 10 ppGpp molecules in the decamer. ppGpp is known to mediate the stringent response, which occurs in response to nutrient deprivation. The alarmone strongly inhibited LdcI enzymatic activity. This inhibition is important for modulating the consumption of lysine in cells during acid stress under nutrient limiting conditions. Hence, our data provide direct evidence for a link between the bacterial acid stress and stringent responses.

Summary Variant surface antigens play an important role in the pathogenesis of Plasmodium falciparum malaria. To date, intensive work has mainly focused on the role in parasite virulence of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) encoded by the var multigene family. Two other multigene families coding for STEVOR and RIFIN have recently also been shown to be expressed in the invasive merozoite as well as on the surface of the infected erythrocyte, implicating them as potential parasite virulence factors. Here we report that STEVOR is an erythrocyte-binding protein recognizing Glycophorin C on the red blood cell (RBC) surface. STEVOR expression on the RBC leads to PfEMP1-independent rosette formation, while antibodies targeting STEVOR in the merozoite can effectively inhibit invasion. Our results suggest a novel role of STEVOR in enabling infected erythrocytes at the schizont stage to bind uninfected erythrocytes to form rosettes, thereby protecting released merozoites from immune detection.