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Principal Investigator: Minolfa C Prieto
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2022
Award: $235,276
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT/SUMMARY
The severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), etiologic agent of the COVID-19, is the
cause of the current worldwide pandemic with unprecedented public health issues. The lung is the most
severely injured organ by SARS-CoV-2, but the kidney appears to be damaged as well. In 90% of patients with
COVID-19 on mechanical ventilation, acute kidney injury (AKI) occurs early, leading to poor prognosis and high
in-hospital mortality.
Angiotensin (Ang) converting ezyme-2 (ACE2), a member of the renin-angiotensin system, opposes Ang II
actions and exerts beneficial CV effects. There is mounting evidence that ACE-2, acts as a major entry
receptor for SARS-CoV-2. Because ACE2 is expressed in proximal tubules, podocytes, mesangial cells,
parietal epithelium of Bowman’s capsule and collecting ducts, it is critical to elucidate the effects of COVID-19
in the development of AKI. Animal models have been used extensively during previous outbreaks of SARS-
CoV to model disease progression and to test vaccines and therapeutics. Non-human primates (NHPs) are
ideally suited to model respiratory viral infections in humans primarily due to their similarities in anatomy and
immunologic responses. Chad J. Roy, PhD (Director of Infectious Disease Aerobiology, Tulane National
Primate Research Center, and Co-Investigator of this project) has recently generated novel and translational
NHP models of COVID-19 using SARS-CoV-2 infection via nasal/intratracheal inoculation, which is able to
reproduce the rapid clinical deterioration seen in people with severe COVID-19. In this pilot exploratory study,
we propose to assess urine transcriptomics in two novel NHP (Rhesus macaque and African green) models of
SARS-2-CoV-2 infection and their associations with early markers of AKI. Our overall hypothesis is that,
because ACE2 may play a critical role in COVID-19-induced kidney injury, changes in urinary transcriptional
signatures are associated with alterations of urinary early kidney injury markers and reflect the effects of
SARS-CoV-2 on kidney ACE2-expressing cells and renal function. Using urine transcriptomics assessed by
single-cell RNA-sequencing in ACE2-expressing cells isolated from urines collected during early infection,
progression, and recovery phases of COVID-19, urinary measurements of kidney injury markers (EGF, MCP-1,
NGAL), and clinical parameters of kidney function, we propose the following Specific aim: To test the
hypothesis that the effects of SARS-CoV2 on the kidney are evidenced by changes of urine transcriptomics
and accompanied by early excretion of kidney injury markers in NHPs with SARS-CoV-2 infection by mean of:
A) To assess the temporal changes of urinary kidney injury markers during early infection, progression, and
recovery phases of COVID-19. B) To determine whether urinary excretion of early kidney injury markers
precede clinical parameters of kidney impairment and AKI; and C) To examine changes of urine
transcriptomics in ACE2-expressing cells at a single-cell resolution during COVID-19. The success of the
proposed study will help to elucidate the value of gene expression–based cell type enrichment analyses in
urine as initial signals of renal injury during the progression of COVID-19.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><72-kDa Gelatinase><72-kDa Type IV Collagenase><72kD type IV Collagenase><Acute><Acute Renal Failure with Renal Papillary Necrosis><Affect><African><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><AngII><Angiotensin II><Angiotensins><Animal Model><Animal Models and Related Studies><Anthelone U><Biological Markers><Blood Serum><Bowman's Capsule><CCL2><CCL2 gene><COVID-19><COVID-19 infection><COVID-19 virus><COVID19><COVID19 infection><COVID19 virus><CV-19><CV19><Causality><Cell Body><Cell Communication and Signaling><Cell Function><Cell Process><Cell Signaling><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Chad><Chemokine, CC Motif, Ligand 2><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Markers><CoV-2><CoV2><Communicable Diseases><Complication><Coronaviridae><Coronavirus><Creatinine><Critical Illness><Critically Ill><Death><Detection><Deterioration><Development><Disease Outbreaks><Disease Progression><Disease model><Doctor of Philosophy><Duct><Duct (organ) structure><Early Intervention><Epidermal Growth Factor><Epidermal Growth Factor-Urogastrone><Epithelial><Etiology><Excretory function><Expression Signature><Family><Gelatinase A><Gelatinase Neutrophil><Gene Expression><Gene Expression Profile><Generalized Growth><Glomerular capsule structure><Growth><Growth Agents><Growth Factor><Growth Substances><Hospital Mortality><Human><IFN-gamma-Inducing Factor><IGIF><IL-1 Gamma><IL-18><IL-1g><IL18 Protein><IL1F4><Immune response><Immunological response><Impairment><In-house Mortalities><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inhospital Mortality><Injury to Kidney><Interferon-gamma-Inducing Factor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 Proprotein><Interleukin-1 Gamma><Interleukin-18><Interleukin-18 Precursor><Intracellular Communication and Signaling><Investigators><Kidney><Kidney Diseases><Kidney Urinary System><Lung><Lung Respiratory System><M mulatta><M. mulatta><MCAF><MCP-1><MCP1><MGC12320><MMP-2><Macaca mulatta><Malpighian Capsule><Matrix Metalloproteinase-2><Measurement><Mechanical ventilation><Modeling><Modern Man><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Nasal><Nasal Passages Nose><Nephropathy><Nephrotoxic><Nose><Organ System><Outbreaks><Outcome><Parietal><Patients><Persons><Ph.D.><PhD><Phase><Plasminogen Activator><Play><Prevalence><Primates><Primates Mammals><Prognosis><Proteins Growth Factors><Proteinuria><Public Health><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recovery><Renal Disease><Renal function><Renin-Angiotensin System><Research><Research Personnel><Researchers><Resolution><Respiratory System, Nose, Nasal Passages><Rhesus Macaque><Rhesus Monkey><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYA2><Sampling><Serum><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A2><Structure><Subcellular Process><Testing><Therapeutic><Tissue Growth><Transforming Growth Factors><Tubular><Tubular formation><Tumor Growth Factors><U-PA receptor><Urine><Urine Urinary System><Urogastrone><Urokinase Plasminogen Activator Receptor><Urokinase Receptor><Urokinase-type Plasminogen Activator Receptor><Viral Respiratory Tract Infection><Virus><Visceral Epithelial Cell><Work><Wuhan coronavirus><acute kidney injury><base><beta-Urogastrone><bio-markers><biologic marker><biological signal transduction><biomarker><body system><cardiovascular effects><causation><cell type><chronic kidney disease><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><critical injury><cystatin C><cytokine release syndrome><cytokine storm><devastating injury><developmental><disease causation><disorder model><evaluate vaccines><excretion><gene expression pattern><gene expression signature><glomerular function><glomerular visceral epithelial cell><hCoV19><host response><immune system response><immunoresponse><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><injury to organs><kidney disorder><kidney function><kidney injury><kidney injury molecule 1><kidney toxicity><mechanical respiratory assist><mechanically ventilated><member><mesangial cell><model of animal><model organism><mortality><nCoV2><nephrotoxicity><next generation><non-human primate><nonhuman primate><novel><ontogeny><organ injury><pandemic><pandemic disease><podocalyxin><podocyte><post gamma-globulins><post-gamma-protein><pro-urokinase receptor><pulmonary><rat KIM-1 protein><receptor><renal><renal KIM-1><renal disorder><renal injury><scRNA-seq><severe acute respiratory syndrome-CoV><severe injury><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><success><systemic inflammation><systemic inflammatory response><tool><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomics><transforming growth factors Animal growth regulators><uPAR receptor><urinary><vaccine evaluation><vaccine screening><vaccine testing><viral respiratory infection>