Acid Stress Response Mechanisms of Group B Streptococci

Abstract

Group B streptococcus (GBS) is a leading cause of neonatal mortality and morbidity in the United States and Europe. It is part of the vaginal microbiota in up to 30% of pregnant women and can be passed on to the newborn through perinatal transmission. GBS has the ability to survive in multiple different host niches. The pathophysiology of this bacterium reveals an outstanding ability to withstand varying pH fluctuations of the surrounding environments inside the human host. GBS host pathogen interations include colonization of the acidic vaginal mucosa, invasion of the neutral human blood or amniotic fluid, breaching of the blood brain barrier as well as survival within the acidic phagolysosomal compartment of macrophages. However, investigations on GBS responses to acid stress are limited. Technologies, such as whole genome sequencing, genome-wide transcription and proteome mapping facilitate large scale identification of genes and proteins. Mechanisms enabling GBS to cope with acid stress have mainly been studied through these techniques and are summarized in the current review.

Keywords: Streptococcus agalactiae; acid resistance; low pH; molecular mechanisms; stress response.

Figure 1

Depicted are typical host environments and their respective pH values that GBS can colonize and infect. Parts of the figure designed by Freepik.

Figure 2

Acid stress responses in Streptococcus agalactiae (Group B streptococci, GBS) under low pH. GBS possess different defense mechanisms to cope with low pH. They include the Arginine deiminase system (ADI), an F-ATPase transporter, transporter of the BCCT family, chaperones and proteases, SodA, and a NRAMP-type transporter. The Arginine deiminase system (ADI) comprises three units: an arginine deiminase (AD), ornithine carbamoyltransferase (OTC) and carbamate kinase (CK). Arginine is taken up from the extracellular environment and cleaved by AD into citrulline and ammonia. Citrulline is further cleaved to yield ornithine and carbamoyl phosphate by the action of OTC. Finally, CK cleaves carbamoyl phosphate into carbon dioxide and ammonia, thereby generating an alkaline microenvironment. Proton pumps like the F-ATPase represent the most direct approach to counteract acid stress by transporting protons outside the cell to keep a proper level of intracellular pH. Under low pH, the F-ATPase system is induced to pump out protons extracellularly in order to maintain the alkalinity of the intracellular cytoplasm. Additional mechanisms include repair or prevention of acid damage in macromolecules by chaperones and proteases, such as Dnak, GroES, and CLp. Metal ion homeostasis also takes part in the acid response as the NRAMP metal ion symporter takes up Mn²⁺ and expels protons out of the cell. The osmotic stress is tightly controlled as well through the up-regulation of the glycine betaine osmoregulation system where choline and glycine betaine (a powerful osmoprotectant) are taken up by transporters of the BCCT (Betaine/Carnitine/Choline Transporter) family. Defense mechanisms to avoid the damaging effects of superoxide species generated during acid stress are mainly exerted through the activity of the streptococcal superoxide dismutase (SOD).