Tag: macrophages

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence.

Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation.

However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition.

Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.

Source: Huot N, Planchais C, Rosenbaum P, Contreras V, Jacquelin B, Petitdemange C, Lazzerini M, Beaumont E, Orta-Resendiz A, Rey FA, Reeves RK, Le Grand R, Mouquet H, Müller-Trutwin M. SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells. Nat Immunol. 2023 Nov 2. doi: 10.1038/s41590-023-01661-4. Epub ahead of print. PMID: 37919524. https://www.nature.com/articles/s41590-023-01661-4 (Full text)

SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels

Abstract:

COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration.

In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1β, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including pro-atherogenic cytokine secretion.

Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events.

Source: Eberhardt N, Noval MG, Kaur R, Sajja S, Amadori L, Das D, Cilhoroz B, Stewart O, Fernandez DM, Shamailova R, Guillen AV, Jangra S, Schotsaert M, Gildea M, Newman JD, Faries P, Maldonado T, Rockman C, Rapkiewicz A, Stapleford KA, Narula N, Moore KJ, Giannarelli C. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels. bioRxiv [Preprint]. 2023 Aug 15:2023.08.14.553245. doi: 10.1101/2023.08.14.553245. PMID: 37645908; PMCID: PMC10461985. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461985/ (Full text)

In severe first episode major depressive disorder, psychosomatic, chronic fatigue syndrome, and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity.

Abstract:

Background: Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors.

Aims: To delineate the impact of ACE+NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles.

Methods: ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls.

Results: Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated).

Partial Least Squares analysis shows that ACE+NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor.

Conclusions: The physiosomatic and FF symptoms of FE-MDMD are partly caused by immuneassociated neurotoxicity due to Th-1 polarization, T helper-1, and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.

Source: Michael Maes, Abbas F Almulla, Bo Zhou, Ali Abbas Abo Algon, Pimpayao Sodsai. In severe first episode major depressive disorder, psychosomatic, chronic fatigue syndrome, and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity. ResearchGate [Preprint] https://www.researchgate.net/publication/372940821_In_severe_first_episode_major_depressive_disorder_psychosomatic_chronic_fatigue_syndrome_and_fibromyalgia_symptoms_are_driven_by_immune_activation_and_increased_immune-associated_neurotoxicity (Full text)

Lymphocyte phenotype and function in the chronic fatigue syndrome

Abstract:

Lymphocytes of 18 patients meeting the Centers for Disease Control (CDC) case definition for the chronic fatigue syndrome (CFS), 10 similar, chronically fatigued patients not fully conforming to the CDC case definition, and 17 matched, healthy individuals were studied to determine the presence of abnormalities of peripheral cell phenotype and function.

Extensive phenotypic analyses of B- and T-cell subsets, natural killer (NK) cells, and macrophages were performed using single-, dual-, and three-color flow cytometry. Compared to controls, in CFS patients the percentage of CD4 T cells and CD4,CD45RA, or naive T cells, was reduced. The CD4,CD45RO, or memory T-cell, subset was numerically normal but expressed increased levels of adhesion markers (CD29, CD54, and CD58). CFS patient lymphocytes showed reduced proliferative responses to phytohemagglutinin, concanavalin A, and staphylococcal enterotoxin B. Lymphocytes from fatigue patients not meeting the CDC definition showed similar abnormalities.

These data indicate that peripheral T cells manifest an increased state of differentiation in CFS and related conditions. This may arise as a consequence of an underlying neuropsychiatric and/or neuroendocrine disorder or because of exposure to antigens or superantigens of an infectious agent.

 

Source: Straus SE, Fritz S, Dale JK, Gould B, Strober W. Lymphocyte phenotype and function in the chronic fatigue syndrome. J Clin Immunol. 1993 Jan;13(1):30-40. http://www.ncbi.nlm.nih.gov/pubmed/8095270