T Cell Immunity and the Quest for Protective Vaccines against Staphylococcus aureus Infection

Abstract

Staphylococcus aureus is a wide-spread human pathogen, and one of the top causative agents of nosocomial infections. The prevalence of antibiotic-resistant S. aureus strains, which are associated with higher mortality and morbidity rates than antibiotic-susceptible strains, is increasing around the world. Vaccination would be an effective preventive measure against S. aureus infection, but to date, every vaccine developed has failed in clinical trials, despite inducing robust antibody responses. These results suggest that induction of humoral immunity does not suffice to confer protection against the infection. Evidence from studies in murine models and in patients with immune defects support a role of T cell-mediated immunity in protective responses against S. aureus. Here, we review the current understanding of the mechanisms underlying adaptive immunity to S. aureus infections and discuss these findings in light of the recent S. aureus vaccine trial failures. We make the case for the need to develop anti-S. aureus vaccines that can specifically elicit robust and durable protective memory T cell subsets.

Keywords: Staphylococcus aureus; T cell-mediated immunity; antibodies; tissue-resident memory T cells; vaccine.

Figure 1

The immune response against S. aureus. Pattern recognition receptors (TLR2/NOD2/TLR9) expressed on innate immune cells such as macrophages (Mac) and dendritic cells (DC) at the infection site respond to S. aureus pathogen-related molecular patterns (LTA, peptidoglycan (PGN), and unmethylated CpG DNA). This interaction leads to the release of cytokines and chemokines (IL-1β, TNF-α, MIP-1α, and GM-CSF), which attracts neutrophils to the site of infection. Neutrophils mediate bacteria killing and clearance via reactive oxygen species (ROS), anti-microbial peptides (AMPs), neutrophil extracellular traps (NETs), and enzymatic digestion by hydrolases and proteinases. After interacting with S. aureus, Mac and DC can migrate to draining lymph nodes to present the antigen to naïve T cells. This interaction causes T cells to undergo functional differentiation, which culminates with the generation of IFNγ and IL-17-producing cells. IFNγ can activate Mac and DC to enhance antigen presentation (among other inflammatory functions). The expression of IL-17 facilitates neutrophil recruitment. The anti-inflammatory cytokines TGFβ and IL-10 can also be induced upon infection and could play both protective (limiting damage) or inhibitory (limiting immune response) roles, depending on the route of infection. Additionally, T_FH cells could differentiate in response to the initial infection and could interact with B cells so as to foster the production of anti-staphylococcal antibodies that enable the opsonization of bacteria or neutralize staphylococcal toxins.

Figure 2

A model for potential roles of T_RM in protecting against S. aureus infection. Given the poor induction of long-lasting protective immunity to S. aureus infections, it is possible that natural S. aureus infection (broken blue arrows) fails to lead to the development of T_RM cells. Vaccination strategies (green arrows) proven to induce protective T_RM responses against another bacterial infection [112] could be employed to promote the induction of protective T_RM cells. If generated upon vaccination, S. aureus-specific T_RM cells could produce IL-17A and IFNγ leading to neutrophil recruitment and subsequent bacterial clearance upon re-infection of sites such as the skin and soft tissues.