Document text
Principal Investigator: Irina Budunova
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $206,917
Funding agency: National Institute of Allergy and Infectious Diseases
COVID-19 continues to be a global catastrophe despite development of anti-SARS-CoV-2 vaccines. This is due
to the worldwide limited vaccine availability, vaccination hesitancy, and the emergence of new variants of SARS-
CoV-2. Moreover, there is a lack of complete knowledge about SARS-CoV-2 biology, including potential
transmission routes and variable pathogenesis, especially in ethnic groups, such as African American (AA) and
Hispanic/Latino that were disproportionally affected by COVID-19 compared to White Non-Hispanic (WNH)
population. The role of biological factors contributing to high infection, hospitalization, and death rates in these
groups remains to be investigated. Cell entry of SARS-CoV-2 depends on binding of the viral spike (S) protein
to the host cell receptor ACE2 and its priming/cleavage by host protease TMPRSS2. It is well accepted that the
main route of the SARS CoV-2 entry into the body is via respiratory epithelial cells. However, cells in other
tissues/organs including the heart, kidney, pancreas, eye and skin (mostly epidermis) also express ACE2 and
TMPRSS2. Some recent studies indicate that skin could be directly targeted by SARS-CoV-2. Indeed, viral RNA
and capsid proteins were detectable in skin biopsies. Importantly, some inflammatory skin diseases, such as
psoriasis and atopic dermatitis, significantly increased the risk of COVID-19. This correlates with the findings
that ACE2 and TMPRSS2 expression was increased in lesional skin of psoriasis patients as well as in wounded
skin. In addition, COVID-19 is associated with dermatological immediate or sometimes persistent manifestations
which could occur because of direct (topical) or systemic (via circulating virus) infection by SARS-CoV-2.
Nevertheless, the potential role of human healthy or inflamed skin in SARS-CoV-2 entry and COVID-19
pathogenesis has not been addressed. It is known that TNF-α, IL-6, IL-1β, and IFN-γ cytokines are involved in
the development of different inflammatory skin diseases and their level is increased during cytokine storm
frequently associated with viremia, multi-organ failure, and development of severe deadly COVID-19
.
In our pilot
experiments, we showed that combination of TNF-α + IL-6 + IL-1β + INF-γ strongly induced expression of ACE2
and TMPRSS2 in 3D human skin equivalents (3D-HSE) made from primary human epidermal keratinocytes
(NHEK). Based on these novel findings, we hypothesize that inflamed skin could be infected by wild type SARS-
CoV-2 virus and its emerging mutated variants, and that higher infection rates reported for specific ethnic
populations may depend on higher expression levels of proteins involved in SARS-CoV-2 cell entry. To test these
hypotheses, we will use pseudotyped Spike (S) protein-containing reporter lentiviruses, 2D- and 3D-HSE
cultures made from AA, Hispanic and WNH keratinocytes pretreated with cytokine cocktails related to COVID-
19 cytokine storm (TNF-α+IL-6+IL-1b+INF-γ) or cytokines proven to induce pro-psoriasis (IL17+IL22+TNFa) or
pro-atopic dermatitis (IL4+IL13) molecular and morphological changes in in vitro skin models.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><3-D><3-Dimensional><3D><3D cell culture><3D culture><ACE2><Acute><Address><African American><African American group><African American individual><African American people><African American population><African Americans><Afro American><Afroamerican><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor 1 Gene><B-Cell Stimulatory Factor-2><BCDF><BSF-1 Gene><BSF-2><BSF1 Gene><BSF2><Beta Proprotein Interleukin 1><Binding><Biologic Factor><Biological Factors><Biology><Body Tissues><COVID burden><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 affected><COVID-19 associated cytokine storm><COVID-19 burden><COVID-19 consequence><COVID-19 cytokine storm><COVID-19 disease burden><COVID-19 effect><COVID-19 health burden><COVID-19 impact><COVID-19 impacted><COVID-19 induced cytokine storm><COVID-19 infected patient><COVID-19 infection><COVID-19 pathogenesis><COVID-19 patient><COVID-19 positive patient><COVID-19 related burden><COVID-19 related cytokine storm><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 virus><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><CV-19><Cachectin><Capsid Proteins><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chicken Pox><Chickenpox><Chronic><CoV-2><CoV2><Coat Proteins><Communities><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Cutaneous Disorder><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Death Rate><Dermatologic><Dermatologic biopsy><Dermatological><Dermatoses><Development><Disparities><Disparity><Disseminated Neurodermatitis><Epidermis><Epithelial Cells><Epitheliasin Gene><Esteroproteases><Ethnic Group><Ethnic Origin><Ethnic People><Ethnic Population><Ethnic individual><Ethnicity><Ethnicity People><Ethnicity Population><Eye><Eyeball><Future><Gene Expression><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glycoproteins><HPGF><Heart><Hepatocyte-Stimulating Factor><Herpes Simplex><Herpes Simplex Infections><Herpes Zoster><Herpes simplex disease><Herpes zoster disease><Herpesvirus hominis disease><Hispanic><Human><Hybridoma Growth Factor><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-1 beta><IL-1 β><IL-1-b><IL-13><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-1β><IL-22><IL-4 Gene><IL-6><IL1-Beta><IL1-β><IL13><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL1B Protein><IL1F2><IL1β><IL4><IL4 gene><IL6 Protein><Immune Evasion><Immune Interferon><In Vitro><Individual><Infection><Infectious Skin Diseases><Inflammation><Inflammatory><Inflammatory Response><Interferon Gamma><Interferon Type II><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin 1beta><Interleukin-1 beta><Interleukin-13><Interleukin-17><Interleukin-1β><Interleukin-4 Gene><Interleukin-4 Precursor Gene><Interleukin-6><Intracellular Communication and Signaling><Kidney><Kidney Urinary System><Knowledge><Latino><Lentivirinae><Lentivirus><Lycopersicon esculentum><MGI-2><MOF syndrome><Macrophage-Derived TNF><Messenger RNA><Modeling><Modern Man><Molecular><Molecular Interaction><Molluscum contagiosum virus><Monocyte-Derived TNF><Morphology><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Mutate><Mutation><Myeloid Differentiation-Inducing Protein><Nasal><Nasal Passages Nose><Non-Hispanic><Non-Polyadenylated RNA><Nonhispanic><Nose><Not Hispanic or Latino><Organ><PRSS10><Pancreas><Pancreatic><Pathogenesis><Patients><Peptidases><Peptide Hydrolases><Plasmacytoma Growth Factor><Population><Preinterleukin 1 Beta><Prevention><Property><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Psoriasis><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Race><Races><Racial Group><Receptor Cell><Recovery><Reporter><Reporting><Respiratory Epithelium><Respiratory System, Nose, Nasal Passages><Ribonucleic Acid><Role><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated cytokine storm><SARS-CoV-2 burden><SARS-CoV-2 cytokine storm><SARS-CoV-2 disease burden><SARS-CoV-2 induced cytokine storm><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 infection burden><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related cytokine storm><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Shingles><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Diseases><Skin Diseases and Manifestations><Skin Manifestations><Socioeconomic Factors><Solanum lycopersicum><Structure of respiratory epithelium><Surface><Symptoms><TMPRSS2><TMPRSS2 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Tissues><Tomatoes><Transmission><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Variant><Variation><Varicella><Viral><Viral Coat Proteins><Viral Outer Coat Protein><Viremia><Virus><Work><Wound Repair><Wuhan coronavirus><Zona><Zoster><access to vaccination><access to vaccines><airway epithelium><allergic dermatitis><allergic eczema><angiotensin converting enzyme 2><angiotensin converting enzyme II><biological signal transduction><corona virus><coronavirus disease 2019><coronavirus disease 2019 associated cytokine storm><coronavirus disease 2019 consequence><coronavirus disease 2019 cytokine storm><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease 2019 induced cytokine storm><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related cytokine storm><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 impact><coronavirus disease-19 pathogenesis><coronavirus disease-19 patient><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cutaneous biopsy><cutaneous disease><cutaneous infection><cutaneous wound><cytokine><cytokine release syndrome><cytokine storm><dermal disease><dermal disorder><dermal wound><developmental><ethnic subgroup><ethnicity group><experiment><experimental research><experimental study><experiments><genome mutation><hCoV19><herpes simplex virus 1 infection><herpes simplex virus infection><herpes zona><hesitant to vaccination><hospitalization rates><immune evasive><in vitro Model><infected skin><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infection rate><innovate><innovation><innovative><interferon beta 2><interleukin-22><keratinocyte><lFN-Gamma><mRNA><mortality rate><mortality ratio><multiorgan failure><multiple organ system failure><mutant><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><novel><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><programs><psoriasiform><psoriatic><racial><racial background><racial origin><racial population><racial subgroup><rate of infection><receptor binding><receptor bound><renal><respiratory tract epithelium><response><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><severe acute respiratory syndrome coronavirus 2 associated cytokine storm><severe acute respiratory syndrome coronavirus 2 cytokine storm><severe acute respiratory syndrome coronavirus 2 induced cytokine storm><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related cytokine storm><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><skin biopsy><skin disorder><skin infection><skin wound><social role><socio-economic factors><three dimensional><three dimensional cell culture><tissue wound><transcriptome sequencing><transcriptomic sequencing><transmission process><vaccination access><vaccination availability><vaccination hesitancy><vaccine access><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine availability><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccine hesitancy><vaccine hesitant><vaccines preventing COVID><vaccines to prevent COVID><viraemia><viral RNA><viral sepsis><virus RNA><virusemia><wound><wound healing><wound recovery><wound resolution><wounding><wounds>