The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen <i>Listeria monocytogenes</i>

Witter, Alexandra R.; Okunnu, Busola; Berg, Rance E.

doi:10.4049/jimmunol.1600599

Cited by 104 publications

(91 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The most striking histological difference between ⌬inlP and wild-type infections was the degree of decidual necrosis. Tissue necrosis in vivo correlates with a widespread infiltration of neutrophils that are recruited to contain bacterial infection (79). Consistent with this, we observed bacterial foci, neutrophil infiltration, and tissue necrosis in the decidua (Fig.…”

Section: Discussionsupporting

confidence: 86%

InlP, a New Virulence Factor with Strong Placental Tropism

et al. 2016

View full text Add to dashboard Cite

Intrauterine infection is a major detriment for maternal-child health and occurs despite local mechanisms that protect the maternal-fetal interface from a wide variety of pathogens. The bacterial pathogen Listeria monocytogenes causes spontaneous abortion, stillbirth, and preterm labor in humans and serves as a model for placental pathogenesis. Given the unique immunological environment of the maternal-fetal interface, we hypothesized that virulence determinants with placental tropism are required for infection of this tissue. We performed a genomic screen in pregnant guinea pigs that led to the identification of 201 listerial genes important for infection of the placenta but not maternal liver. Among these genes was lmrg1778 (lmo2470), here named inlP, predicted to encode a secreted protein that belongs to the internalin family. InlP is conserved in virulent L. monocytogenes strains but absent in Listeria species that are nonpathogenic for humans. The intracellular life cycle of L. monocytogenes deficient in inlP (⌬inlP) was not impaired. In guinea pigs and mice, InlP increased the placental bacterial burden by a factor of 3 log 10 while having only a minor role in other maternal organs. Furthermore, the ⌬inlP strain was attenuated in intracellular growth in primary human placental organ cultures and trophoblasts. InlP is a novel virulence factor for listeriosis with a strong tropism for the placenta. This virulence factor represents a tool for the development of new modalities to prevent and treat infection-related pregnancy complications.T he immunological environment of the maternal-fetal interface is unique because protection of the fetus from pathogens has to be balanced with tolerance of the fetus by the maternal immune system (1, 2). How this is accomplished is one of the major enigmas of mammalian reproduction. Contrary to the long-standing hypothesis that the pregnant mother is immunocompromised (3), recent evidence suggests that the maternal immune system is intricately regulated during pregnancy, and the placenta is well guarded against infection (4-6). A few predominantly intracellular microbes are able to infect the placenta and cause pregnancy complications such as preterm labor, fetal damage, and death (5, 7). Given the unique immunological environment of the maternal-fetal interface and the inability of many pathogens to colonize the placenta, we hypothesized that specific virulence determinants are required for microbes to survive and replicate in this tissue.Listeria monocytogenes is a facultative intracellular bacterial pathogen that causes spontaneous abortion, preterm labor, and stillbirth in humans and other mammals (8, 9). There are ϳ1,600 human cases in the United States per year, and about one-third of these cases are pregnancy associated (10). L. monocytogenes is also extremely amenable to experimental analysis and therefore has been exploited over the past 5 decades to understand host-pathogen interactions of intracellular microbes (11, 12). L. monocytogenes can infect a wide variety ...

show abstract

Section: Discussionsupporting

confidence: 86%

InlP, a New Virulence Factor with Strong Placental Tropism

et al. 2016

View full text Add to dashboard Cite

show abstract

“…4F-G ) in vitro , effectively ruling out cell-intrinsic autophagy defects in Hmgb1 ΔLysM immune cells. Given the profound impairments of bacterial clearance in Hmgb1 ΔLysM animals, we next tested bactericidal activities of isolated polymorphonuclear granulocytes (PMNs) as well as primary monocytes, two main effector cell types of innate anti-bacterial immunity (26,38), which are targeted by LysM-Cre (27), from Hmgb1 f/f and Hmgb1 ΔLysM mice. We observed a similar ∼40-50% reduction of listeria in the presence of either Hmgb1 f/f or Hmgb1 ΔLysM PMNs in vitro after 4 hours ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Leukocyte-derived High-mobility group box 1 controls innate immune responses against Listeria monocytogenes

Volmari

Foelsch

Yan

et al. 2019

Preprint

View full text Add to dashboard Cite

24 High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern with key 25 proinflammatory functions following tissue injury. Moreover, HMGB1 neutralization was shown to 26 alleviate LPS-induced shock, suggesting a role for the protein as a master therapeutic target for 27 inflammatory and infectious diseases. Here, we report that HMGB1 neutralization impedes 28 immune responses to Listeria monocytogenes, a wide-spread bacterium with pathogenic 29 relevance for humans and rodents. Using genetic deletion strategies and neutralizing antibodies, 30 we demonstrate that hepatocyte HMGB1, a major driver of post-necrotic inflammation in the liver, 31 is dispensable for pathogen defense during moderately severe infection with listeria. In contrast, 32 antibody-mediated HMGB1 neutralization and HMGB1 deficiency in myeloid cells effectuate rapid 33 and uncontrolled bacterial dissemination in mice despite preserved basic leukocyte functionality 34 and autophagy induction. During overwhelming infection, hepatocyte injury may contribute to 35 increased HMGB1 serum levels and excessive inflammation in the liver, supporting context-36 dependent roles for HMGB1 from different cellular compartments during infection. We provide 37 mechanistic evidence that HMGB1 from circulating immune cells contributes to the timely 38 induction of hepatic immune regulatory gene networks, early inflammatory monocyte recruitment 39 to the liver and promotion of neutrophil survival, which are mandatory for pathogen control. In 40 summary, our data establish HMGB1 as a critical co-factor in the immunological clearance of 41 listeria, and argue against HMGB1 neutralization as a universal therapeutic strategy for sepsis. 42 43 44 45 46 47 48 3 49 Author summary50 High-mobility group box 1 (HMGB1) is an abundantly expressed nucleoprotein with signaling 51 properties following secretion or release into the extracellular space. Given its central immune-52 regulatory roles during tissue injury and LPS-induced septic shock, interventions aimed at 53 HMGB1 signaling have been advocated as therapeutic options for various disease conditions. 54 Here, we show that antibody-mediated HMGB1 neutralization interferes with immunological 55 defense against Listeria monocytogenes, a gram-positive bacterium with high pathogenic 56 relevance for rodents and humans, effectuating uncontrolled bacterial growth and inflammation.57 Using conditional knockout animals, we demonstrate that while leukocyte functionality is 58 preserved in HMGB1-deficient myeloid cells, HMGB1 released in response to Listeria triggers 59 hepatic inflammatory monocyte recruitment and activation of transcriptional immune networks 60 required for the early control of bacterial dissemination. Hepatocyte HMGB1, a key driver of post-61 necrotic inflammation in the liver, is dispensable for the immune response during moderately 62 severe infection, but likely contributes to excessive hepatitis when infection is uncontrolled and 63 cellular injury is high. We demonstrate a critical and non...

show abstract

“…However, in the last couple decades it has become apparent neutrophils possess several sophisticated mechanisms for detecting and eliminating pathogens. Detailed discussions on the functions of neutrophils during steady state and inflammatory environments can be found in the following reviews [108–111]. …”

Section: Myeloid Responsesmentioning

confidence: 99%