Porcine Alveolar Macrophages' Nitric Oxide Synthase-Mediated Generation of Nitric Oxide Exerts Important Defensive Effects against Glaesserella parasuis Infection.

Qi Cao,Xiangru Wang,Zhao Wen,Huanchun Chen,Yujin Lv,Huan Wang,Wenbin Wei,Xuwang Cai,Xiaojuan Xu

doi:10.3390/pathogens8040234

Abstract

Glaesserella parasuis is a habitual bacterium of pigs’ upper respiratory tracts. Its infection initiates with the invasion and colonization of the lower respiratory tracts of pigs, and develops as the bacteria survive host pulmonary defenses and clearance by alveolar macrophages. Alveolar macrophage-derived nitric oxide (NO) is recognized as an important mediator that exerts antimicrobial activity as well as immunomodulatory effects. In this study, we investigated the effects and the signaling pathway of NO generation in porcine alveolar macrophages 3D4/21 during G. parasuis infection. We demonstrated a time and dose-dependent generation of NO in 3D4/21 cells by G. parasuis, and showed that NO production required bacterial viability and nitric oxide synthase 2 upregulation, which was largely contributed by G. parasuis-induced nuclear factor-κB signaling’s activation. Moreover, the porcine alveolar macrophage-derived NO exhibited prominent bacteriostatic effects against G. parasuis and positive host immunomodulation effects by inducing the production of cytokines and chemokines during infection. G. parasuis in turn, selectively upregulated several nitrate reductase genes to better survive this NO stress, revealing a battle of wits during the bacteria–host interactions. To our knowledge, this is the first direct demonstration of NO production and its anti-infection effects in alveolar macrophages with G. parasuis infection.

Highlights

Glaesserella parasuis is the causative agent of porcine Glässer’s disease, which is characterized by polyarthritis, fibrinous polyserositis and meningitis [1,2]
The porcine alveolar macrophage cell line 3D4/21 was induction of nitric oxide (NO) was observed over time
A faster generation of NO detected following a higher multiplicity of infection (MOI) applied

Summary

Introduction

Glaesserella parasuis is the causative agent of porcine Glässer’s disease, which is characterized by polyarthritis, fibrinous polyserositis and meningitis [1,2] It is considered one of the most important opportunistic bacterial pathogens in nursery piglets, with the ability to cause high morbidity and mortality in China [3]. Based on the infection dynamics, G. parasuis infections initiate from the invasion and colonization of the lower respiratory tract of pigs, and breakthrough host pulmonary defenses and clearance [6]. During these interaction processes, G. parasuis has to compete with lung-resident alveolar macrophages, which play essential roles in the first-line of host defense. The innate immune system employs pathogen-associated molecular patterns (PAMPs), such as Toll-like receptors and nucleotide oligomerization domain-like receptors, to detect bacterial products and trigger innate immune responses [10,11]

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Conclusion