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The Role of Early-Life Viral Respiratory Illness in Development of Childhood Asthma Endotypes: the PRIMERO II study

Award Number: R01HL138626
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/24/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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The Role of Early-Life Viral Respiratory Illness in Development of Childhood Asthma Endotypes: the PRIMERO II study - PROJECT SUMMARY Childhood asthma is the most common chronic illness in children, driven by complex gene– environment interactions. Among environmental factors, severe lower respiratory tract illnesses (sLRIs) in infancy—particularly from respiratory syncytial virus (RSV) and human rhinovirus (HRV)—are among the strongest predictors of asthma. Yet whether sLRIs play a causal role or merely unmask a pre-existing susceptibility remains unresolved. The PRIMERO birth cohort was established to address this critical gap by prospectively enrolling 2,100 children and capturing airway biosamples from birth through early childhood. By integrating dense viral surveillance, genetic profiling, and airway transcriptomics at birth, illness, and follow-up, PRIMERO offers a uniquely powerful platform to disentangle the relationship between sLRIs and asthma. Preliminary findings support the hypothesis that sLRIs both reveal and reshape asthma risk. Infants who later developed HRV-sLRIs—but not RSV-sLRIs—showed strong downregulation of immune-related genes at birth. In contrast, RSV-sLRIs were associated with a high risk of sLRIs vs. upper RIs regardless of birth expression. A PRIMERO transcriptome-wide association study (TWAS) identified 130 genes whose genetically regulated airway expression conferred sLRI risk, including established asthma loci (TSLP, IL1RL1, FADS2). Children with prior sLRIs also showed persistent airway changes at age 2—downregulation of ciliated-cell genes and upregulation of multiple inflammatory networks—implicating sLRI-driven remodeling in asthma pathogenesis. Based on these data, we hypothesize that asthma endotypes arise through distinct but overlapping mechanisms—(1) inborn epithelial or immune dysfunction, (2) sLRI-driven airway remodeling, and (3) genetic modulation of these processes. Aim 1 will test whether birth airway dysfunction predisposes to asthma, and whether sLRIs mediate this effect. Aim 2 will define how sLRI-induced airway remodeling leads to asthma endotypes. Aim 3 will determine how genetic risk converges with sLRIs to drive asthma through molecular regulation. These studies will define causal mechanisms linking early infection and genetic risk to asthma, enabling novel strategies for early-life prediction, prevention, and intervention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,319,983 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	6	5/8/2026	COMPETING CONTINUATION	$1,319,983
														Subtotal = $1,319,983

Grand Total All Awards = $1,319,983

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The Role of Early-Life Viral Respiratory Illness in Development of Childhood Asthma Endotypes: the PRIMERO II study

Award Number: R01HL138626

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/24/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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