Pic-Producing Escherichia coli Induces High Production of Proinflammatory Mediators by the Host Leading to Death by Sepsis.

Itaynara L Dutra,Rosa M Silva,Eduardo M De Sousa,Lucilene A Silva,Márcia C G Maciel,Lorena G Araújo,Waldir P Elias,Flávia R F Nascimento,Afonso G Abreu,Johnny R Nascimento,Patrícia C S Alves,André A M Vale,Liana O Trovão,Ana Carolina M Santos,Yago A Lima,Raissa G Assunção

doi:10.3390/ijms21062068

Abstract

Escherichia coli is an important pathogen responsible for a variety of diseases. We have recently shown that Pic, a serine protease secreted by E. coli, mediates immune evasion by the direct cleavage of complement molecules. The aim of this study was to investigate the action of a Pic-producing bacteria in a murine model of sepsis. Mice were infected with Pic-producing E. coli (F5) or F5∆pic mutant. Animal survival was monitored for five days, and a subset of mice was euthanized after 12 h for sample acquisition. The inoculation of Pic-producing bacteria induced 100% death within 24 h. The colony forming units count in the organs was significantly higher in F5. Hematological analysis showed a decrease of total leukocytes. Nitric oxide and cytokines were detected in serum, as well as on peritoneal lavage of the F5 group in higher levels than those detected in the other groups. In addition, immunophenotyping showed a decrease of activated lymphocytes and macrophages in the F5 group. Therefore, Pic represents an important virulence factor, allowing the survival of the bacterium in the bloodstream and several organs, as well as inducing a high production of proinflammatory mediators by the host, and concomitantly a cellular immunosuppression, leading to sepsis and death.

Highlights

Sepsis is known as a life-threatening organ dysfunction resulting from an overwhelming immune response triggered by invading pathogens [1]
Since protein involved in colonization (Pic) is able to degrade important biological substrates, the aim of this work was to evaluate the ability of the serine protease Pic produced by E. coli to induce lethal sepsis in animals submitted to intraperitoneal inoculation of bacteria
There was no death in the F5∆pic3 ogf 1r9oup, suggesting that the death is 1r0e0l%atmeodrtatolitythweithpinre2s4ehnacfeteroifnfPecitcion(.FHigowuerveer1, )t.here was no death in the F5Δpic group, suggesting that the death is related to the presence of Pic (Figure 1)

Summary

Introduction

Sepsis is known as a life-threatening organ dysfunction resulting from an overwhelming immune response triggered by invading pathogens [1]. This process begins when pathogen-associated molecular patterns (PAMPs) are recognized by pattern recognition receptors (PRRs) from host immune cells, which results in several protein phosphorylation cytoplasmic reactions following transcriptions of genes encoding inflammatory mediators, such as cytokines, chemokines, and nitric oxide synthase [2]. Comparing the mortality of hospitalized patients in intensive care units (ICUs) from different countries, a high mortality was observed in Brazil (56.1%) followed by Argentina (46.6%), United States of America (33%), Canada (30.3%), and Australia (22%) [7]. In Brazil, the costs resulting from these hospitalizations, in 2015 alone, were approximately R$ 400 million [9]

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