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J Immunol. 2019 Sep 1;203(5):1298-1312. doi: 10.4049/jimmunol.1900104. Epub 2019 Jul 29.

Immune Response Resetting in Ongoing Sepsis.

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Integrated Center for Pediatric OncoHaematological Research, State University of Campinas, Campinas 13083-888, Brazil;
Integrated Center for Pediatric OncoHaematological Research, State University of Campinas, Campinas 13083-888, Brazil.
Surgery Department, Santa Casa School of Medical Sciences, São Paulo 01221-020, Brazil.
School of Engineering, Mackenzie Presbyterian University, São Paulo 01302-907, Brazil.
Mass Spectrometry Research and Development Laboratory, Health Sciences Department, Waters Corporation, Barueri 06455-020, Brazil.
Thomson Mass Spectrometry Laboratory, Institute of Chemistry, State University of Campinas, Campinas 13083-859, Brazil; and.
Boldrini Children's Center, Campinas 13083-210, Brazil.


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.

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