Immune Response Resetting in Ongoing Sepsis

Abstract

Cure of severe infections, sepsis, and septic shock with antimicrobial drugs is a challenge because morbidity and mortality in these conditions are essentially caused by improper immune response. We have tested the hypothesis that repeated reactivation of established memory to pathogens may reset unfavorable immune responses. We have chosen for this purpose a highly stringent mouse model of polymicrobial sepsis by cecum ligation and puncture. Five weeks after priming with a diverse Ag pool, high-grade sepsis was induced in C57BL/6j mice that was lethal in 24 h if left untreated. Antimicrobial drug (imipenem) alone rescued 9.7% of the animals from death, but >5-fold higher cure rate could be achieved by combining imipenem and two rechallenges with the Ag pool (p < 0.0001). Antigenic stimulation fine-tuned the immune response in sepsis by contracting the total CD3 + T cell compartment in the spleen and disengaging the hyperactivation state in the memory T subsets, most notably CD8 + T cells, while preserving the recovery of naive subsets. Quantitative proteomics/lipidomics analyses revealed that the combined treatment reverted the molecular signature of sepsis for cytokine storm, and deregulated inflammatory reaction and proapoptotic environment, as well as the lysophosphatidylcholine/phosphatidylcholine ratio. Our results showed the feasibility of resetting uncontrolled hyperinflammatory reactions into ordered hypoinflammatory responses by memory reactivation, thereby reducing morbidity and mortality in antibiotic-treated sepsis. This beneficial effect was not dependent on the generation of a pathogen-driven immune response itself but rather on the reactivation of memory to a diverse Ag pool that modulates the ongoing response.

Immune Response Resetting as a Novel Strategy to Overcome SARS-CoV-2–Induced Cytokine Storm

“…Ideally, this approach should be combined with other therapeutic strategies directed at reducing the pathogen load. In our earlier work, imipenem had this role (121). Perhaps remdesivir, or any other antiviral drug that proves to be effective, could play this part in the context of SARS-CoV-2 infection.…”

“…In the case of sepsis, the strong secondary activation and memory response would generate a new hypoinflammatory context that takes over the antipathogen response and is more conducive to disease resolution. Indeed, we have recently demonstrated that repeated reactivation of established T cell memory to a pool of diverse and mostly unrelated pathogens may reset unfavorable immune responses in a mouse model of polymicrobial high-grade sepsis induced by cecum ligation and puncture (121). This off-target revaccination produced .5-fold higher sepsis cure rate when employed in combination with imipenem as compared with the survival achieved with the use of this antibiotic alone.…”

“…Both immune response resetting (usually particulate Ags) and trained immunity (often live or attenuated microbes) allow antigenic stimuli to generate broader protection, but they also differ in how this effect is achieved. Trained immunity relies on epigenetic/metabolic reprograming of innate immune cells, whereas immune response resetting achieves off-target protection through memory T cell reactivation (113,121). Thus, the nature of the heterologous protection may be innate induced or adaptive induced, depending on how the antigenic stimulation occurs.…”

“…In a nutshell, immune response resetting could be achieved by systemic and repeated reactivation of established memory to a pool of well-defined, unrelated Ags against which most humans have preformed immunity (121). Instead of one new agent against which the immune system might occasionally mount a disorganized, innate-biased, hyperinflammatory response, it now likely "sees" the pathogen diluted in a pool of multiple and diverse attackers for which there are circulating T cell memory precursors that may be promptly called from "retirement."…”

“…Additionally, the molecular signatures of the cytokine storm and the proapoptotic environment were reverted. This outcome was not dependent on eliciting a pathogen-specific new immune response but rather on the repeated reactivation of T cell memory to a diverse Ag pool capable of modulating the already ongoing response against sepsis (121).…”