In this study, we tested the hypothesis that the conserved bacterial IgaA-family protein, GumB, mediates microbial pathogenesis associated with
Serratia marcescens
ocular infections through regulation of the Rcs stress response system. The role of the Rcs system and bacterial stress response systems for microbial keratitis is not known, and the role of IgaA proteins in mammalian pathogenesis models has only been tested with partial function allele variants of
Salmonella
. Here we observed that a Rcs-activated
gumB
mutant had a >50-fold reduction in proliferation compared to the wild type within rabbit corneas at 48 h, and demonstrated a notable reduction in inflammation based on inflammatory signs, including the absence of hypopyons, and proinflammatory markers measured at the RNA and protein levels. The
gumB
mutant phenotypes could be complemented by wild-type
gumB
on a plasmid. We observed that bacteria with inactivated of the Rcs stress response system induced high levels of ocular inflammation and restored corneal virulence to the
gumB
mutant. The high virulence of the Δ
rcsB
mutant was dependent upon the ShlA cytolysin transporter ShlB. Similar results were found testing the cytotoxic effects of WT and mutant bacteria on a human corneal epithelial cell line
in vitro
. Together, these data indicate that GumB regulates virulence factor production through the Rcs system and this overall stress response system is a key mediator of a bacterium’s ability to induce vision-threatening keratitis.