Background Covid-19 clinical expression is pleiomorphic, severity is related to age and comorbidities such as diabetes and hypertension, and pathophysiology involves aberrant immune activation and lymphopenia. We wondered if the myeloid compartment was affected during Covid-19 and if monocytes and macrophages could be infected by SARS-CoV-2. Methods Monocytes and monocyte-derived macrophages from Covid-19 patients and controls were infected with SARS-CoV-2, and extensively investigated with immunofluorescence, viral RNA extraction and quantification, total RNA extraction followed by reverse transcription and q-PCR using specific primers, supernatant cytokines (IL-10, TNF-α, IL-1β, IFN-β, TGF-β1 and IL-6), flow cytometry. The effect of M1- versus M2-type or no polarization prior to infection was assessed. Results SARS-CoV-2 efficiently infected monocytes and MDMs but their infection is abortive. Infection was associated with immunoregulatory cytokines secretion and the induction of a macrophagic specific transcriptional program characterized by the upregulation of M2-type molecules. In vitro polarization did not account for permissivity to SARS-CoV-2, since M1- and M2-type MDMs were similarly infected. In Covid-19 patients, monocytes exhibited lower counts affecting all subsets, decreased expression of HLA-DR, and increased expression of CD163, irrespective of severity. Conclusion SARS-CoV-2 drives monocytes and macrophages to induce host immunoparalysis for the benefit of Covid-19 progression.

Background An unbiased approach of SARS-CoV-2-induced immune dysregulation has not been undertaken so far. We aimed to identify previously unreported immune markers able to discriminate COVID-19 patients from healthy controls and to predict mild and severe disease. Methods An observational, prospective, multicentric study was conducted in patients with confirmed COVID-19: mild/moderate (n=7) and severe (n=19). Immunophenotyping of whole blood leukocytes was performed in patients upon hospital ward or intensive care unit admission and in healthy controls (n=25). Clinically relevant associations were identified through unsupervised analysis. Results Granulocytic (neutrophil, eosinophil and basophil) markers were enriched during COVID-19 and discriminated between mild and severe patients. Increased counts of CD15 +CD16 + neutrophils, decreased granulocytic expression of integrin CD11b, and Th2-related CRTH2 downregulation in eosinophils and basophils established a COVID-19 signature. Severity was associated with the emergence of PDL1 checkpoint expression in basophils and eosinophils. This granulocytic signature was accompanied by monocyte and lymphocyte immunoparalysis. Correlation with validated clinical scores supported pathophysiological relevance. Conclusion Phenotypic markers of circulating granulocytes are strong discriminators between infected and uninfected individuals as well as between severity stages. COVID-19 alters the frequency and functional phenotypes of granulocyte subsets with the emergence of CRTH2 as a disease biomarker.

To date, the Covid-19 pandemic affected more than 18 million individuals and caused more than 690, 000 deaths. Its clinical expression is pleiomorphic and severity is related to age and comorbidities such as diabetes and hypertension. The pathophysiology of the disease relies on aberrant activation of immune system and lymphopenia that has been recognized as a prognosis marker. We wondered if the myeloid compartment was affected in Covid-19 and if monocytes and macrophages could be infected by SARS-CoV-2. We show here that SARS-CoV-2 efficiently infects monocytes and macrophages without any cytopathic effect. Infection was associated with the secretion of immunoregulatory cytokines (IL-6, IL-10, TGF-β) and the induction of a macrophagic specific transcriptional program characterized by the upregulation of M2-type molecules. In addition, we found that in vitro macrophage polarization did not account for the permissivity to SARS-CoV-2, since M1-and M2-type macrophages were similarly infected. Finally, in a cohort of 76 Covid-19 patients ranging from mild to severe clinical expression, all circulating monocyte subsets were decreased, likely related to massive emigration into tissues. Monocytes from Covid-19 patients exhibited decreased expression of HLA-DR and increased expression of CD163, irrespective of the clinical status. Hence, SARS-CoV-2 drives circulating monocytes and macrophages inducing immunoparalysis of the host for the benefit of Covid-19 disease progression.

We demonstrated that all trauma patients had impaired circadian rhythms of cortisol, cytokines, leukocytes, and clock genes. Early circadian disruption was associated with the occurrence of sepsis and might be a marker of sepsis severity.

The intracellular bacterium Coxiella burnetii is responsible for Q fever, an infectious disease that increases the risk of abortion, preterm labor, and stillbirth in pregnant women. It has been shown that C. burnetii replicates in BeWo trophoblast cell line and inhibits the activation and maturation of decidual dendritic cells. Although tissue macrophages are known to be targeted by C. burnetii, no studies have investigated the interplay between placental macrophages and C. burnetii. Here, CD14+ macrophages from 46 full-term placentas were isolated by positive selection. They consisted of a mixed population of maternal and fetal origin as shown by genotype analysis. We showed that C. burnetii organisms infected placental macrophages after 4 h. When these infected macrophages were incubated for an additional 9-day culture, they completely eliminated organisms as shown by quantitative PCR. The ability of placental macrophages to form multinucleated giant cells was not affected by C. burnetii infection. The transcriptional immune response of placental macrophages to C. burnetii was investigated using quantitative real-time RT-PCR on 8 inflammatory and 10 immunoregulatory genes. C. burnetii clearly induced an inflammatory profile. Interestingly, the production by placental macrophages of interferon-γ, a cytokine known to be involved in efficient immune responses, was dramatically increased in response to C. burnetii. In addition, a clear correlation between interferon-γ production and C. burnetii elimination was found, suggesting that macrophages from full-term placentas eliminate C. burnetii under the control of an autocrine production of interferon-γ.

The circadian rhythm of the body temperature (CRBT) is a marker of the central biological clock that results from multiple complex biological processes. In mammals, including humans, the body temperature displays a strict circadian rhythm and has to be maintained within a narrow range to allow optimal physiological functions. There is nowadays growing evidence on the role of the temperature circadian rhythm on the expression of the molecular clock. The CRBT likely participates in the phase coordination of circadian timekeepers in peripheral tissues, thus guaranteeing the proper functioning of the immune system. The disruption of the CRBT, such as fever, has been repeatedly described in diseases and likely reflects a physiological process to activate the molecular clock and trigger the immune response. On the other hand, temperature circadian disruption has also been described as associated with disease severity and thus may mirror or contribute to immune dysfunction. The present review aims to characterize the potential implication of the temperature circadian rhythm on the immune response, from molecular pathways to diseases. The origin of CRBT and physiological changes in body temperature will be mentioned. We further review the immune biological effects of temperature rhythmicity in hosts, vectors, and pathogens. Finally, we discuss the relationship between circadian disruption of the body temperature and diseases and highlight the emerging evidence that CRBT monitoring would be an easy tool to predict outcomes and guide future studies in chronotherapy.

The host defense against pathogens varies among individuals. Among the factors influencing host response, those associated with circadian disruptions are emerging. These latter depend on molecular clocks, which control the two partners of host defense: microbes and immune system. There is some evidence that infections are closely related to circadian rhythms in terms of susceptibility, clinical presentation and severity. In this review, we overview what is known about circadian rhythms in infectious diseases and update the knowledge about circadian rhythms in immune system, pathogens and vectors. This heuristic approach opens a new fascinating field of time-based personalized treatment of infected patients.

Globally, it is estimated that nearly 10 million people sustain severe brain injuries leading to hospitalization and/or death every year. Amongst survivors, traumatic brain injury (TBI) results in a wide variety of physical, emotional and cognitive deficits. The most common cognitive deficit associated with TBI is memory loss, involving impairments in spatial reference and working memory. However, the majority of research thus far has characterized the deficits associated with TBI on either reference or working memory systems separately, without investigating how they interact within a single task. Thus, we examined the effects of TBI on short-term working and long-term reference memory using the radial 8-arm maze (RAM) with a sequence of four baited and four unbaited arms. Subjects were given 10 daily trials for 6 days followed by a memory retrieval test 2 weeks after training. Multiple training trials not only provide robust training, but also test the subjects' ability to frequently update short-term memory while learning the reference rules of the task. Our results show that TBI significantly impaired short-term working memory function on previously acquired spatial information but has little effect on long-term reference memory. Additionally, TBI significantly increased working memory errors during acquisition and reference memory errors during retention testing 2 weeks later. With a longer recovery period after TBI, the robust RAM training mitigated the reference memory deficit in retention but not the short-term working memory deficit during acquisition. These results identify the resiliency and vulnerabilities of short-term working and long-term reference memory to TBI in the context of robust training. The data highlight the role of cognitive training and other behavioral remediation strategies implicated in attenuating deficits associated with TBI.