Infection and Immunity

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ISSN / EISSN : 0019-9567 / 1098-5522
Published by: American Society for Microbiology (10.1128)
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Jesse M. Hall, Graham J. Bitzer, Megan A. DeJong, Jason Kang, Ting Y. Wong, M. Allison Wolf, Justin R Bevere, ,
Infection and Immunity; https://doi.org/10.1128/iai.00346-21

Abstract:
Pertussis is a respiratory disease caused by the Gram-negative pathogen, Bordetella pertussis ( Bp ). The transition from a whole cell pertussis vaccine (wP; DTP) to an acellular pertussis vaccine (aP; DTaP; Tdap) correlates with an increase in pertussis cases, despite widespread vaccine implementation and coverage, and it is now appreciated that the protection provided by aP rapidly wanes. To recapitulate the localized immunity observed from natural infection, mucosal vaccination with aP was explored using the coughing rat model of pertussis. Overall, our goal was to evaluate the route of vaccination in the coughing rat model of pertussis. Immunity induced by both oral gavage (OG) and intranasal (IN) vaccination of aP in Bp challenged rats over a nine-day infection was compared to intramuscular (IM)-wP and IM-aP immunized rats that were used as positive controls. Our data demonstrate that mucosal immunization of aP resulted in production of anti- Bp IgG antibody titers similar to IM-wP and IM-aP vaccinated controls post-challenge. IN-aP also induced anti- Bp IgA antibodies in the nasal cavity. Immunization with IM-wP, IM-aP, IN-aP, and OG-aP immunization protected against Bp induced cough, while OG-aP immunization did not protect against respiratory distress. Mucosal immunization by both IN and OG administration protected against acute inflammation and decreased bacterial burden in the lung compared to mock vaccinated challenge (MVC) rats. The data presented in this study suggests that mucosal vaccination with aP can induce a mucosal immune response and provide protection against Bp challenge. This study highlights the potential benefits and uses of the coughing rat model of pertussis; however, further questions regarding waning immunity still require additional investigation.
R. Villarreal, H.S. Manzer, ,
Infection and Immunity; https://doi.org/10.1128/iai.00340-21

Abstract:
Streptococcus agalactiae (Group B Streptococcus , GBS), is an opportunistic pathogen capable of causing invasive disease in susceptible individuals including the newborn. Currently GBS is the leading cause of meningitis in the neonatal period. We have recently shown that GBS interacts directly with host type III intermediate filament vimentin to gain access to the central nervous system. This results in characteristic meningeal inflammation and disease progression; however, the specific role of vimentin in the inflammatory process is unknown. Here we investigate the contribution of vimentin to the pathogenesis of GBS meningitis. We show that a CRISPR targeted deletion of vimentin in human cerebral microvascular endothelial cells (hCMEC) reduced GBS induction of neutrophil attractants IL-8 and CXCL-1, as well as NFκB activation. We further show that inhibition of vimentin localization also prevented similar chemokine activation by GBS. One known chemokine regulator is the nucleotide-binding oligomerization domain containing protein 2 (NOD2), which is known to interact directly with vimentin. Thus, we hypothesized that NOD2 would also promote GBS chemokine induction. We show that GBS infection induced NOD2 transcription in hCMEC comparable to the muramyl dipeptide (MDP) NOD2 agonist, and the chemokine induction was reduced in the presence of a NOD2 inhibitor. Using a mouse model of GBS meningitis we also observed increased NOD2 transcript and NOD2 activation in brain tissue of infected mice. Lastly, we show that NOD2 mediated IL8 and CXCL1 induction required vimentin, further indicating the importance of vimentin in mediating inflammatory responses in brain endothelium.
Savannah E. Sanchez, Alan G. Goodman,
Infection and Immunity; https://doi.org/10.1128/iai.00135-21

Abstract:
Coxiella burnetii , the causative agent of Query (Q) fever in humans, is an obligate intracellular bacterium. C. burnetii can naturally infect a broad range of host organisms (e.g., mammals and arthropods) and cell types. This amphotropic nature of C. burnetii , in combination with its ability to utilize both glycolytic and gluconeogenic carbon sources, suggests that the pathogen relies on metabolic plasticity to replicate in nutritionally diverse intracellular environments. To test the significance of metabolic plasticity in C. burnetii host cell colonization, C. burnetii intracellular replication in seven distinct cell lines was compared between a metabolically competent parental strain and a mutant, Cb Δ pckA, unable to undergo gluconeogenesis. Both the parental strain and Cb Δ pckA exhibited host cell-dependent infection phenotypes, which were influenced by alterations to host glycolytic or gluconeogenic substrate availability. Because the nutritional environment directly impacts host cell physiology, our analysis was extended to investigate the response of C. burnetii replication in mammalian host cells cultivated in a novel physiological medium based on the nutrient composition of mammalian interstitial fluid, Interstitial Fluid-modeled Medium (IFmM). An infection model based on IFmM resulted in exacerbation of a replication defect exhibited by Cb Δ pckA in specific cell lines. Cb Δ pckA was also attenuated during infection of an animal host. Overall, the study underscores that gluconeogenic capacity aids C. burnetii amphotropism and that the amphotropic nature of C. burnetii should be considered when resolving virulence mechanisms in this pathogen.
A Hashim, A Alsam, M. A. Payne, J Aduse-Opoku, M. A. Curtis, S Joseph
Infection and Immunity; https://doi.org/10.1128/iai.00309-21

Abstract:
Periodontal disease is considered to arise from an imbalance in the interplay between the host and its commensal microbiota, characterized by inflammation, destructive periodontal bone loss and a dysbiotic oral microbial community. The neutrophil is a key component of defence of the periodontium: defects in their number or efficacy of function predisposes individuals to development of periodontal disease. Paradoxically, neutrophil activity, as part of a deregulated inflammatory response, is considered to be an important element in the destructive disease process. In this investigation we examined the role the neutrophil plays in the regulation of the oral microbiota, by analysis of the microbiome composition in mice lacking the CXCR2 neutrophil receptor required for recruitment to the periodontal tissues. A breeding protocol was employed which ensured that only the oral microbiota of wild type (CXCR2 +/+ ) mice was transferred to subsequent generations of wild type, heterozygote and homozygote littermates. In the absence of neutrophils, the microbiome undergoes a significant shift in total load and composition compared to when normal levels of neutrophil recruitment into the gingival tissues occur, and this is accompanied by a significant increase in periodontal bone pathology. However, transfer of the oral microbiome of CXCR2 -/- mice into germ free CXCR2 +/+ mice led to restoration of the microbiome to the wild type CXCR2 +/+ composition and the absence of pathology. These data demonstrate that the composition of the oral microbiome is inherently flexible and is governed to a significant extent by the genetics and resultant phenotype of the host organism.
Ozcan Gazioglu, Banaz O. Kareem, Muhammad Afzal, , , , Peter W. Andrew,
Infection and Immunity; https://doi.org/10.1128/iai.00400-21

Abstract:
During its progression from the nasopharynx to other sterile and non-sterile niches of its human host, Streptococcus pneumoniae must cope with changes in temperature. We hypothesised that the temperature adaptation is an important facet of pneumococcal survival in the host. Here, we evaluated the effect of temperature on pneumococcus and studied the role of glutamate dehydrogenase (GdhA) in thermal adaptation associated with virulence and survival. Microarray analysis revealed a significant transcriptional response to changes in temperature, affecting the expression of 252 genes in total at 34°C and 40°C relative to at 37°C. One of the differentially regulated genes was gdhA, which is upregulated at 40°C and downregulated at 34°C relative to 37°C. Deletion of gdhA attenuated the growth, cell size, biofilm formation, pH survival, and biosynthesis of proteins associated with virulence in a temperature-dependent manner. Moreover, deletion of gdhA stimulated formate production irrespective of temperature fluctuation. Finally, Δ gdhA grown at 40°C was less virulent compare to other temperatures or than the wild type at the same temperature in a Galleria mellonella infection model, suggesting that GdhA is required for pneumococcal virulence at elevated temperature.
Aimaiti Yasen, Wujianan Sun, Abudusalamu Aini, Tuerganaili Aji, Yingmei Shao, Hui Wang, Kun Li, Wending Li, Chuanshan Zhang, Ayifuhan Ahan, et al.
Infection and Immunity; https://doi.org/10.1128/iai.00297-21

Abstract:
Human cystic echinococcosis, caused by the larval stage of echinococcus granulus sensu lato , has been reported a near-cosmopolitan zoonotic disease. Various infiltrating immune cells gather around the lesion and produce lesion microenvironment, however cellular composition and heterogeneity in hepatic cystic echinococcosis lesion microenvironment are incompletely understood. Here, 81,865 immune cells isolated from peripheral blood, peri-lesion liver tissue, and adjacent normal liver tissue from four cystic echinococcosis patients were profiled using single-cell RNA sequencing. We identified 23 discrete cell populations, and found distinct differences in infiltrating immune cells between tissue environments. Despite the significant similarity between peri-lesion and adjacent normal liver tissue-resident immune cells, the cellular proportions of innate lymphocyte 2 and plasmacytoid dendritic cells were higher in peri-lesion liver tissue. Interestingly, the immunosuppressive gene NFKBIA was up-regulated in these cells. Seven subsets of CD4 + T cell populations were found, and there were more Treg-CD4 + T and Th2-CD4 + T cells in peri-lesion tissue than those in adjacent normal tissue. There was close contact between CD4 + T cells and ILC2 and pDCs cells, which caused up-regulation of genes related to positive immune activity in adjacent normal liver tissue. However, expression of genes related to immunosuppression, especially the immune inhibitory checkpoint gene NKG2A/HLA-E, was obviously higher in peri-lesion tissue, suggesting that cellular interaction resulted in an inhibitory microenvironment in the CE lesion. This work offers new insights into the transcriptional heterogeneity of infiltrating immune cells in hepatic cystic echinococcosis lesion microenvironment at single-cell level, and provides potential target signatures for diagnosis and immunotherapies.
Liam Fitzsimmons, Tina Clark,
Infection and Immunity; https://doi.org/10.1128/iai.00371-21

Abstract:
Rickettsia rickettsii , the causative agent of Rocky Mountain spotted fever, is an enzootic, obligate intracellular bacterial pathogen. Nitric oxide (NO) synthesized by the inducible nitric oxide synthase (iNOS) is a potent antimicrobial component of innate immunity and has been implicated in the control of virulent Rickettsia spp. in diverse cell types. In this study, we examined the antibacterial role of NO on R. rickettsii . Our results indicate that NO challenge dramatically reduces R. rickettsii adhesion through the disruption of bacterial energetics. Additionally, NO-treated R. rickettsii were unable to synthesize protein or replicate in permissive cells. Activated, NO-producing macrophages restricted R. rickettsii infections, but inhibition of iNOS ablated the inhibition of bacterial growth. These data indicate that NO is a potent anti-rickettsial effector of innate immunity that targets energy generation in these pathogenic bacteria to prevent growth and subversion of infected host cells.
Amy Pham, Emma L. Ledger, Carrie F. Coggon, , David W. Reid, , Daniel J. Smith,
Infection and Immunity; https://doi.org/10.1128/iai.00412-21

Abstract:
Pseudomonas aeruginosa is one of the principal pathogens implicated in respiratory infections of patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously, we demonstrated that impaired serum-mediated killing of P. aeruginosa was associated with increased severity of respiratory infections in patients with non-CF bronchiectasis. This inhibition was mediated by high titres of O-antigen-specific IgG2 antibodies that cloak the surface of the bacteria, blocking access to the membrane. Infection related symptomatology was ameliorated in patients by using plasmapheresis to remove the offending antibodies. To determine if these inhibitory ‘cloaking antibodies’ were prevalent in patients with CF, we investigated 70 serum samples from patients with P. aeruginosa infection, and five without P. aeruginosa infection. Thirty-two percent of patients had serum that inhibited the ability of healthy control serum to kill P. aeruginosa . Here we demonstrate that this inhibition of killing requires O-antigen expression. Furthermore, we reveal that while IgG alone can inhibit the activity of healthy control serum, O-antigen specific IgA in patient sera can also inhibited serum-killing. We found that antibody affinity, not just titre, was also important in the inhibition of serum-mediated killing. These studies provide novel insight into cloaking antibodies in human infection and may provide further options in CF and other diseases for treatment of recalcitrant P. aeruginosa infections.
Giuseppe Ancona, Laura Alagna, Andrea Lombardi, Emanuele Palomba, Valeria Castelli, Giulia Renisi, Daniele Dondossola, Massimo Iavarone, Antonio Muscatello, Andrea Gori, et al.
Infection and Immunity; https://doi.org/10.1128/iai.00376-21

Abstract:
Liver transplantation (LT) is a life-saving strategy for patients with end-stage liver disease, hepatocellular carcinoma and acute liver failure. LT success can be hampered by several short-term and long-term complications. Among them, bacterial infections, especially due to multidrug-resistant germs, are particularly frequent with a prevalence between 19 and 33% in the first 100 days after transplantation. In the last decades, a number of studies have highlighted how gut microbiota (GM) is involved in several essential functions to ensure the intestinal homeostasis, becoming one of the most important virtual metabolic organs. GM works through different axes with other organs, and the gut-liver axis is among the most relevant and investigated ones. Any alteration or disruption of GM is defined as dysbiosis. Peculiar phenotypes of GM dysbiosis have been associated to several liver conditions and complications, such as chronic hepatitis, fatty liver disease, cirrhosis and hepatocellular carcinoma. Moreover, there is growing evidence of the crucial role of GM in shaping the immune response, both locally and systemically, against pathogens. This paves the way to the manipulation of GM as a therapeutic instrument to modulate the infectious risk and outcome. In this minireview we provide an overview of the current understanding on the interplay between gut microbiota and the immune system in liver transplant recipients and the role of the former in infections.
Mia H. E. Kennedy, Tara P. Brosschot, Katherine M. Lawrence, Rachael D. FitzPatrick, Jenna M. Lane, Grace M. Mariene, James D. Wasmuth,
Infection and Immunity; https://doi.org/10.1128/iai.00225-21

Abstract:
Heligmosomoides polygyrus is a helminth which naturally infects mice and is widely used as a laboratory model of chronic small intestinal helminth infection. While it is known that infection with H. polygyrus alters the composition of the host’s bacterial microbiota, the functional implications of this alteration are unclear. We investigated the impact of H. polygyrus infection on short-chain fatty acid (SCFA) levels in the mouse intestine and sera. We found that helminth infection resulted in significantly upregulated levels of the branched SCFA isovaleric acid, exclusively in the proximal small intestine, which is the site of H. polygyrus colonization. We next set out to test the hypothesis that elevating local levels of isovaleric acid was a strategy used by H. polygyrus to promote its own fitness within the mammalian host. To test this, we supplemented the drinking water of mice with isovalerate during H. polygyrus infection and examined whether this affected helminth fecundity or chronicity. We did not find that isovaleric acid supplementation affected helminth chronicity, however, we found that it did promote helminth fecundity, as measured by helminth egg output in the feces of mice. Through antibiotic-treatment of helminth-infected mice, we found that the bacterial microbiota was required in order to support elevated levels of isovaleric acid in the proximal small intestine during helminth infection. Overall, our data reveal that during H. polygyrus infection there is a microbiota-dependent localized increase in the production of isovaleric acid in the proximal small intestine and this supports helminth fecundity in the murine host.
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