Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect Of Mucosal Fluid From Women With Bacterial Vaginosis On Hiv Trans-infection Mediated By Dendritic Cells

Women with bacterial vaginosis (BV) have a higher risk of HIV transmission but the cause of risk is unknown. Dendritic cells (DC) are implicated in transmission of HIV and we previously observed that DC mature when exposed to mucosal fluid from women with BV. We hypothesized that maturation of DC by BV mucosal fluid would enhance DC-mediated trans-infection of HIV. Monocyte-derived DC (MDDC) were treated with mucosal fluid, incubated with HIVBal, and HIV trans-infection was evaluated. While LPS-treated MDDC increased HIVBal trans-infection, BV fluid reduced trans-infection. HIVBal DNA levels in MDDC were not affected by BV fluid or LPS but productive infection of MDDC was decreased by LPS and BV fluid. Mucosal fluid from women with BV does not increase MDDC-mediated trans-infection suggesting that BV does not increase HIV susceptibility by increasing DC-mediated trans-infection. However, indirect effects of DC maturation on HIV transmission cannot be ruled out. © 2008 Elsevier Inc. All rights reserved.38512227(2004) AIDS Clinical Trials Group Laboratory Manual, , ACTGCavrois, M., Neidleman, J., Kreisberg, J.F., Fenard, D., Callebaut, C., Greene, W.C., Human immunodeficiency virus fusion to dendritic cells declines as cells mature (2006) J. Virol., 80 (4), pp. 1992-1999Chun, T.W., Justement, J.S., Lempicki, R.A., Yang, J., Dennis Jr., G., Hallahan, C.W., Sanford, C., Fauci, A.S., Gene expression and viral production in latently infected, resting CD4+T cells in viremic versus aviremic HIV-infected individuals (2003) Proc. Natl. Acad. Sci. U. S. A., 100 (4), pp. 1908-1913Cohen, C.R., Duerr, A., Pruithithada, N., Rugpao, S., Hillier, S., Garcia, P., Nelson, K., Bacterial vaginosis and HIV seroprevalence among female commercial sex workers in Chiang Mai, Thailand (1995) Aids, 9 (9), pp. 1093-1097de Saint-Vis, B., Fugier-Vivier, I., Massacrier, C., Gaillard, C., Vanbervliet, B., Ait-Yahia, S., Banchereau, J., Caux, C., The cytokine profile expressed by human dendritic cells is dependent on cell subtype and mode of activation (1998) J. Immunol., 160 (4), pp. 1666-1676Edwards, J.N., Morris, H.B., Langerhans' cells and lymphocyte subsets in the female genital tract (1985) Br. J. Obstet. Gynaecol., 92 (9), pp. 974-982Eschenbach, D.A., Davick, P.R., Williams, B.L., Klebanoff, S.J., Young-Smith, K., Critchlow, C.M., Holmes, K.K., Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with bacterial vaginosis (1989) J. Clin. Microbiol., 27 (2), pp. 251-256Fortin, J.F., Cantin, R., Lamontagne, G., Tremblay, M., Host-derived ICAM-1 glycoproteins incorporated on human immunodeficiency virus type 1 are biologically active and enhance viral infectivity (1997) J. Virol., 71 (5), pp. 3588-3596Foti, M., Granucci, F., Ricciardi-Castagnoli, P., A central role for tissue-resident dendritic cells in innate responses (2004) Trends Immunol., 25 (12), pp. 650-654Fredricks, D.N., Fiedler, T.L., Marrazzo, J.M., Molecular identification of bacteria associated with bacterial vaginosis (2005) N. Engl. J. Med., 353 (18), pp. 1899-1911Geijtenbeek, T.B., Kwon, D.S., Torensma, R., van Vliet, S.J., van Duijnhoven, G.C., Middel, J., Cornelissen, I.L., van Kooyk, Y., DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells (2000) Cell, 100 (5), pp. 587-597Granelli-Piperno, A., Delgado, E., Finkel, V., Paxton, W., Steinman, R.M., Immature dendritic cells selectively replicate macrophagetropic (M-tropic) human immunodeficiency virus type 1, while mature cells efficiently transmit both M- and T-tropic virus to T cells (1998) J. Virol., 72 (4), pp. 2733-2737Greenblatt, R.M., Bacchetti, P., Barkan, S., Augenbraun, M., Silver, S., Delapenha, R., Garcia, P., Burns, D., Lower genital tract infections among HIV-infected and high-risk uninfected women: findings of the Women's Interagency HIV Study (WIHS) (1999) Sex Transm. Dis., 26 (3), pp. 143-151Hladik, F., Sakchalathorn, P., Ballweber, L., Lentz, G., Fialkow, M., Eschenbach, D., McElrath, M.J., Initial events in establishing vaginal entry and infection by human immunodeficiency virus type-1 (2007) Immunity, 26 (2), pp. 257-270Hu, J., Gardner, M.B., Miller, C.J., Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells (2000) J. Virol., 74 (13), pp. 6087-6095Hu, Q., Frank, I., Williams, V., Santos, J.J., Watts, P., Griffin, G.E., Moore, J.P., Shattock, R.J., Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue (2004) J. Exp. Med., 199 (8), pp. 1065-1075Izquierdo-Useros, N., Blanco, J., Erkizia, I., Fernandez-Figueras, M.T., Borras, F.E., Naranjo-Gomez, M., Bofill, M., Martinez-Picado, J., Maturation of blood-derived dendritic cells enhances human immunodeficiency virus type 1 capture and transmission (2007) J. Virol., 81 (14), pp. 7559-7570Kawamura, T., Cohen, S.S., Borris, D.L., Aquilino, E.A., Glushakova, S., Margolis, L.B., Orenstein, J.M., Blauvelt, A., Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants (2000) J. Exp. Med., 192 (10), pp. 1491-1500Kawamura, T., Gulden, F.O., Sugaya, M., McNamara, D.T., Borris, D.L., Lederman, M.M., Orenstein, J.M., Blauvelt, A., R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms (2003) Proc. Natl. Acad. Sci. U. S. A., 100 (14), pp. 8401-8406Kawamura, T., Koyanagi, Y., Nakamura, Y., Ogawa, Y., Yamashita, A., Iwamoto, T., Ito, M., Shimada, S., Significant virus replication in Langerhans cells following application of HIV to abraded skin: relevance to occupational transmission of HIV (2008) J. Immunol., 180 (5), pp. 3297-3304Keir, M.E., Francisco, L.M., Sharpe, A.H., PD-1 and its ligands in T-cell immunity (2007) Curr. Opin. Immunol., 19 (3), pp. 309-314Managlia, E.Z., Landay, A., Al-Harthi, L., Interleukin-7 signalling is sufficient to phenotypically and functionally prime human CD4 naive T cells (2005) Immunology, 114 (3), pp. 322-335Managlia, E.Z., Landay, A., Al-Harthi, L., Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway (2006) Virology, 350 (2), pp. 443-452Mares, D., Simoes, J.A., Novak, R.M., Spear, G.T., TLR2-mediated cell stimulation in bacterial vaginosis (2007) J. Reprod. Immunol., 77 (1), pp. 91-99Martin, H.L., Richardson, B.A., Nyange, P.M., Lavreys, L., Hillier, S.L., Chohan, B., Mandaliya, K., Kreiss, J., Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition (1999) J. Infect. Dis., 180 (6), pp. 1863-1868McDonald, D., Wu, L., Bohks, S.M., KewalRamani, V.N., Unutmaz, D., Hope, T.J., Recruitment of HIV and its receptors to dendritic cell-T cell junctions (2003) Science, 300 (5623), pp. 1295-1297McDyer, J.F., Dybul, M., Goletz, T.J., Kinter, A.L., Thomas, E.K., Berzofsky, J.A., Fauci, A.S., Seder, R.A., Differential effects of CD40 ligand/trimer stimulation on the ability of dendritic cells to replicate and transmit HIV infection: evidence for CC-chemokine-dependent and -independent mechanisms (1999) J. Immunol., 162 (6), pp. 3711-3717Myer, L., Denny, L., Telerant, R., Souza, M., Wright Jr., T.C., Kuhn, L., Bacterial vaginosis and susceptibility to HIV infection in South African women: a nested case-control study (2005) J. Infect. Dis., 192 (8), pp. 1372-1380Nugent, R.P., Krohn, M.A., Hillier, S.L., Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation (1991) J. Clin. Microbiol., 29 (2), pp. 297-301Piguet, V., Steinman, R.M., The interaction of HIV with dendritic cells: outcomes and pathways (2007) Trends Immunol., 28 (11), pp. 503-510Pope, M., Betjes, M.G., Romani, N., Hirmand, H., Cameron, P.U., Hoffman, L., Gezelter, S., Steinman, R.M., Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1 (1994) Cell, 78 (3), pp. 389-398Pope, M., Betjes, M.G., Romani, N., Hirmand, H., Hoffman, L., Gezelter, S., Schuler, G., Steinman, R.M., Dendritic cell-T cell conjugates that migrate from normal human skin are an explosive site of infection for HIV-1 (1995) Adv. Exp. Med. Biol., 378, pp. 457-460Reece, J.C., Handley, A.J., Anstee, E.J., Morrison, W.A., Crowe, S.M., Cameron, P.U., HIV-1 selection by epidermal dendritic cells during transmission across human skin (1998) J. Exp. Med., 187 (10), pp. 1623-1631Relloso, M., Puig-Kroger, A., Pello, O.M., Rodriguez-Fernandez, J.L., de la Rosa, G., Longo, N., Navarro, J., Corbi, A.L., DC-SIGN (CD209) expression is IL-4 dependent and is negatively regulated by IFN, TGF-beta, and anti-inflammatory agents (2002) J. Immunol., 168 (6), pp. 2634-2643Romani, N., Reider, D., Heuer, M., Ebner, S., Kampgen, E., Eibl, B., Niederwieser, D., Schuler, G., Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability (1996) J. Immunol. Methods, 196 (2), pp. 137-151Sallusto, F., Lanzavecchia, A., Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha (1994) J. Exp. Med., 179 (4), pp. 1109-1118Sallusto, F., Cella, M., Danieli, C., Lanzavecchia, A., Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products (1995) J. Exp. Med., 182 (2), pp. 389-400Sanders, R.W., de Jong, E.C., Baldwin, C.E., Schuitemaker, J.H., Kapsenberg, M.L., Berkhout, B., Differential transmission of human immunodeficiency virus type 1 by distinct subsets of effector dendritic cells (2002) J. Virol., 76 (15), pp. 7812-7821Schwebke, J.R., Gynecologic consequences of bacterial vaginosis (2003) Obstet. Gynecol. Clin. North Am., 30 (4), pp. 685-694Sewankambo, N., Gray, R.H., Wawer, M.J., Paxton, L., McNaim, D., Wabwire-Mangen, F., Serwadda, D., Konde-Lule, J., HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis (1997) Lancet, 350 (9077), pp. 546-550St John, E.P., Martinson, J., Simoes, J.A., Landay, A.L., Spear, G.T., Dendritic cell activation and maturation induced by mucosal fluid from women with bacterial vaginosis (2007) Clin. Immunol., 125 (1), pp. 95-102Taha, T.E., Hoover, D.R., Dallabetta, G.A., Kumwenda, N.I., Mtimavalye, L.A., Yang, L.P., Liomba, G.N., Miotti, P.G., Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV (1998) Aids, 12 (13), pp. 1699-1706Taha, T.E., Gray, R.H., Kumwenda, N.I., Hoover, D.R., Mtimavalye, L.A., Liomba, G.N., Chiphangwi, J.D., Miotti, P.G., HIV infection and disturbances of vaginal flora during pregnancy (1999) J. Acquir. Immune Defic. Syndr. Human Retrovirol., 20 (1), pp. 52-59Tardif, M.R., Tremblay, M.J., Presence of host ICAM-1 in human immunodeficiency virus type 1 virions increases productive infection of CD4+T lymphocytes by favoring cytosolic delivery of viral material (2003) J. Virol., 77 (22), pp. 12299-12309Thoma-Uszynski, S., Kiertscher, S.M., Ochoa, M.T., Bouis, D.A., Norgard, M.V., Miyake, K., Godowski, P.J., Modlin, R.L., Activation of toll-like receptor 2 on human dendritic cells triggers induction of IL-12, but not IL-10 (2000) J. Immunol., 165 (7), pp. 3804-3810Thurner, B., Roder, C., Dieckmann, D., Heuer, M., Kruse, M., Glaser, A., Keikavoussi, P., Schuler, G., Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application (1999) J. Immunol. Methods, 223 (1), pp. 1-15Turville, S.G., Santos, J.J., Frank, I., Cameron, P.U., Wilkinson, J., Miranda-Saksena, M., Dable, J., Cunningham, A.L., Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells (2004) Blood, 103 (6), pp. 2170-2179(2006) Report on Global AIDS Epidemic 2006, , UNAIDS , UNAIDS. MayVasir, B., Avigan, D., Wu, Z., Crawford, K., Turnquist, S., Ren, J., Kufe, D., Dendritic cells induce MUC1 expression and polarization on human T cells by an IL-7-dependent mechanism (2005) J. Immunol., 174 (4), pp. 2376-238

HAART and risk of tuberculosis in HIV-infected South African children: A multi-site retrospective cohort

SETTING: Four human immunodeficiency virus (HIV) clinics located at South African tertiary hospitals. OBJECTIVE: To assess the effectiveness of highly active antiretroviral therapy (HAART) in reducing incident tuberculosis (TB) in HIV-infected children. DESIGN: Retrospective cohort. RESULTS: A total of 1132 children's records were included in the study. At entry to the cohort, the median (interquartile range [IQR]) age, CD4%, CD4 count and viral load of all children was respectively 6.3 years (4.1-8.8), 15% (9.0-22.2), 576 cells/mm 3 (287-960) and 160 000 copies/ml (54941.5-449683); 75.9% were started on HAART. The male:female ratio was 1:1, and median follow-up time was 1.7 years. In children whose follow-up included both pre-HAART and on-HAART periods, the incidence of clinically diagnosed TB was respectively 21.1 per 100 person-years (py; 95%CI 18.2-24.4) and 6.4/100 py (95%CI 4.8-8.1), and when restricted to confirmed cases, respectively 3.1/100 py (95%CI 2.2-4.2) and 0.8/100 py (95%CI 0.5-1.4). Only 23% of all cases of TB were microbiologically confirmed. Multivariate analyses showed that HAART reduced incident TB by approximately 70%, both for confirmed and all TB cases. CONCLUSIONS: In this high TB burden country, the incidence of diagnosis of TB in HIV-infected children is at least as high as that of adults. HAART reduces incident TB, but further prospective TB preventive and diagnostic studies are urgently needed in children. © 2009 The Union.Articl