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PLoS Pathog ; 17(4): e1009531, 2021 04.
Article in English | MEDLINE | ID: covidwho-1231265


Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including natural killer (NK) cells. Lastly, the ability of Ncr1+ cell derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.

Listeria monocytogenes/immunology , Listeriosis/immunology , Pneumonia/immunology , Animals , Disease Progression , Disease Susceptibility , Female , Interleukin-10/metabolism , Killer Cells, Natural/metabolism , Killer Cells, Natural/physiology , Lipopolysaccharides , Listeria monocytogenes/pathogenicity , Listeriosis/complications , Listeriosis/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mouth Diseases/complications , Mouth Diseases/immunology , Mouth Diseases/microbiology , Mouth Diseases/pathology , Pneumonia/complications , Pneumonia/etiology , Pneumonia/pathology
Front Immunol ; 12: 640644, 2021.
Article in English | MEDLINE | ID: covidwho-1133916


Infection with SARS-CoV-2 can lead to Coronavirus disease-2019 (COVID-19) and result in severe acute respiratory distress syndrome (ARDS). Recent reports indicate an increased rate of fungal coinfections during COVID-19. With incomplete understanding of the pathogenesis and without any causative therapy available, secondary infections may be detrimental to the prognosis. We monitored 11 COVID-19 patients with ARDS for their immune phenotype, plasma cytokines, and clinical parameters on the day of ICU admission and on day 4 and day 7 of their ICU stay. Whole blood stimulation assays with lipopolysaccharide (LPS), heat-killed Listeria monocytogenes (HKLM), Aspergillus fumigatus, and Candida albicans were used to mimic secondary infections, and changes in immune phenotype and cytokine release were assessed. COVID-19 patients displayed an immune phenotype characterized by increased HLA-DR+CD38+ and PD-1+ CD4+ and CD8+ T cells, and elevated CD8+CD244+ lymphocytes, compared to healthy controls. Monocyte activation markers and cytokines IL-6, IL-8, TNF, IL-10, and sIL2Rα were elevated, corresponding to monocyte activation syndrome, while IL-1ß levels were low. LPS, HKLM and Aspergillus fumigatus antigen stimulation provoked an immune response that did not differ between COVID-19 patients and healthy controls, while COVID-19 patients showed an attenuated monocyte CD80 upregulation and abrogated release of IL-6, TNF, IL-1α, and IL-1ß toward Candida albicans. This study adds further detail to the characterization of the immune response in critically ill COVID-19 patients and hints at an increased susceptibility for Candida albicans infection.

Aspergillus fumigatus/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Candida albicans/immunology , Listeria monocytogenes/immunology , SARS-CoV-2/physiology , Aged , Cells, Cultured , Cytokines/metabolism , Disease Susceptibility , Female , Humans , Immune Tolerance , Male , Middle Aged , Programmed Cell Death 1 Receptor/metabolism , Respiratory Distress Syndrome
Front Immunol ; 11: 597433, 2020.
Article in English | MEDLINE | ID: covidwho-983709


Newborns are highly susceptible to infectious diseases. The underlying mechanism of neonatal infection susceptibility has generally been related to their under-developed immune system. Nevertheless, this notion has recently been challenged by the discovery of the physiological abundance of immunosuppressive erythroid precursors CD71+ erythroid cells (CECs) in newborn mice and human cord blood. Here, as proof of concept, we show that these cells are also abundant in the peripheral blood of human newborns. Although their frequency appears to be more variable compared to their counterparts in mice, they rapidly decline by 4 weeks of age. However, their proportion remains significantly higher in infants up to six months of age compared to older infants. We found CD45 expressing CECs, as erythroid progenitors, were the prominent source of reactive oxygen species (ROS) production in both humans and mice. Interestingly, a higher proportion of CD45+CECs was observed in the spleen versus bone marrow of neonatal mice, which was associated with a higher ROS production by splenic CECs compared to their siblings in the bone marrow. CECs from human newborns suppressed cytokine production by CD14 monocytes and T cells, which was partially abrogated by apocynin in vitro. Moreover, the depletion of CECs in neonatal mice increased the number of activated effector immune cells in their spleen and liver, which rendered them more resistant to Listeria monocytogenes infection. This was evident by a significant reduction in the bacteria load in the spleen, liver and brain of treated-mice compared to the control group, which enhanced their survival rate. Our finding highlights the immunoregulatory processes mediated by CECs in newborns. Thus, such tightly regulated immune system in newborns/infants may explain one potential mechanism for the asymptomatic or mild COVID-19 infection in this population.

Antigens, CD/immunology , Erythroid Precursor Cells , Immunosuppression , Listeria monocytogenes/immunology , Listeriosis , Receptors, Transferrin/immunology , Animals , Animals, Newborn , COVID-19/immunology , COVID-19/pathology , Erythroid Precursor Cells/immunology , Erythroid Precursor Cells/pathology , Erythroid Precursor Cells/transplantation , Female , Heterografts , Humans , Infant, Newborn , Listeriosis/immunology , Listeriosis/pathology , Listeriosis/therapy , Male , Mice , Mice, Inbred BALB C , SARS-CoV-2/immunology