Preconditioning with Lipopolysaccharide or Lipoteichoic Acid Protects against Staphylococcus aureus Mammary Infection in Mice

Abstract

Staphylococcus aureus is one of the most causative agents of mastitis and is associated with chronic udder infections. The persistency of the pathogen is believed to be the result of an insufficient triggering of local inflammatory signaling. In this study, the preclinical mastitis model was used, aiming to evaluate if lipopolysaccharide (LPS) or lipoteichoic acid (LTA) preconditioning could aid the host in more effectively clearing or at least limiting a subsequent S. aureus infection. A prototypic Gram-negative virulence factor, i.e., LPS and Gram-positive virulence factor, i.e., LTA were screened whether they were able to boost the local immune compartment. Compared to S. aureus-induced inflammation, both toxins had a remarkable high potency to efficiently induce two novel selected innate immunity biomarkers i.e., lipocalin 2 (LCN2) and chitinase 3-like 1 (CHI3L1). When combining mammary inoculation of LPS or LTA prior to a local S. aureus infection, we were able to modulate the innate immune response, reduce local bacterial loads, and induce either LCN2 or CHI3L1 at 24 h post-infection. Clodronate depletion of mammary macrophages also identified that macrophages contribute only to a limited extend to the LPS/LTA-induced immunomodulation upon S. aureus infection. Based on histological neutrophil influx evaluation, concomitant local cytokine profiles and LCN2/CHI3L1 patterns, the macrophage-independent signaling plays a major role in the LPS- or LTA-pretreated S. aureus-infected mouse mammary gland. Our results highlight the importance of a vigilant microenvironment during the innate immune response of the mammary gland and offer novel insights for new approaches concerning effective immunomodulation against a local bacterial infection.

The Mammary Microenvironment in Mastitis in Humans, Dairy Ruminants, Rabbits and Rodents: A One Health Focus

“…Excitingly, a recent study has demonstrated that, in a murine model, preconditioning the mammary gland with inoculation of LTA or lipopolysaccharide (LPS) modulates the innate immune response to a local S. aureus infection, and reduces the subsequent bacterial burden. By depleting macrophages in this model, the authors showed that this response was partially independent of macrophage signalling and the authors also implicated lipocalin 2 and chitinase 3-like 1 as potential modulators of the innate immune response [ 97 ].…”

“…Mouse models of mastitis provide a tractable system in which the mammary microenvironment can be manipulated in a controlled manner and therefore offer a model in which the effects of new interventions can be more readily elucidated [ 97 , 102 ]. However, some protocols involve weaning of offspring at the time of mastitis induction which causes induction of involution [ 135 ].…”

Staphylococcus aureus Extracellular Vesicles Elicit an Immunostimulatory Response in vivo on the Murine Mammary Gland

“…The bovine strain S. aureus Newbould 305 (Prasad and Newbould, 1968 ; Bouchard et al, 2012 ), hereafter referred to as S. aureus N305, has been used as a model strain for S. aureus mastitis in numerous studies including several from our group (Bouchard et al, 2013 ; Breyne et al, 2014 , 2017a , b ; Peton et al, 2016 ). Despite many efforts dedicated to understand the pathogenesis of S. aureus mastitis, the infectious process is still poorly understood and a better knowledge on host-pathogen interactions is required to allow the development of effective preventive or curative strategies.…”

Impact of bovine lipocalin-2 haplotype on milk composition, somatic cell score and incidence of mastitis in Polish Holstein-Friesian cattle

“…Lipocalin-2 was also shown to exhibit anti-bacterial properties against other bacteria, e.g. Staphylococcus aureus (Robinson et al 2014;Breyne et al 2017). Due to the fact, that mastitis in cows is mostly caused by bacteria such as Escherichia coli, Streptococcus agalactiae or Staphylococcus aureus (Holmberg et al 2012;Jensen et al 2013), it seems that lipocalin-2 should be an essential factor in combating such pathogens.…”