Lukacs Laboratory

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Early Life RSV Infection

Respiratory syncytial virus (RSV) infects nearly all infants by age 2 and is the leading cause of bronchiolitis in children worldwide.  It is estimated by the CDC that up to 125,000 pediatric hospitalizations in the United States each year are due to RSV, at an annual cost of over $700 million. While RSV is especially detrimental in very young infants whose airways are small and easily occluded, RSV has become recognized as an important pathogen in transplant recipients, the elderly, as well as patients with chronic lung disease including asthma and COPD. Although anti-RSV antibodies are available and appear to alleviate severe disease, they perform best when given prophylactically, and recently vaccines are indicated for older children and adults along with maternal vaccination strategy that may or may not alter disease in susceptible infants.  Knowledge of how the early life immune response is generated and “trained” would better inform vaccine efficacy to understand how to best immunize infants. Several epidemiological studies link severe RSV infection with the later development of hyper-reactive airway disease that persists even years after the initial viral infection has resolved and increased the relative risk of developing asthma by 3-5-fold. RSV has also been associated with asthma exacerbations and can cause prolonged episodes of illness. It is likely that RSV, and other viral infections, drive an underlying immune phenotype and early disease with severe RSV is an independent variable for allergic asthma at age 7. The neonatal immune response is immature and evolutionarily skewed away from inflammatory responses in utero to avoid abortive birth.  While recent development of RSV vaccines can protect adults and older children, their efficacy for infants have not been established and may not provide adequate long-term protection in a subset of susceptible infants.  At birth, the immune system must quickly mature and adapt to the new non-sterile environment that includes both pathogenic and environmental stimuli. Previous studies with neonatal RSV infection have demonstrated changes in lungs including mucus production and increased immune cells that persist, including DC and ILC2 that produce IL-5 and IL-13. Few studies have examined how early viral (RSV) infections alter immune responses and subsequent allergen sensitization and lung function. A recent large clinical study in Lancet has indicated that patients who experienced severe lower respiratory tract infection by 2 years of age (RSV the most common) have twice the risk of dying prematurely from respiratory disease.  Thus, early infections can have life-long consequences, possibly including altered lung development and structure that leads to reduced function throughout life.

 


Control Lung

Asthmatic Lung

EL-RSV Exacerbation

 

Publications

  1. Malinczak CA, Fonseca W, Hrycaj SM, Morris SB, Rasky AJ, Yagi K, Wellik DM, Ziegler SF, Zemans RL, Lukacs NW. Early-life pulmonary viral infection leads to long-term functional and lower airway structural changes in the lungs. American journal of physiology Lung cellular and molecular physiology 2024; 326: L280-L291.
  2. Malinczak CA, Schuler CF, Duran AJ, Rasky AJ, Mire MM, Nunez G, Lukacs NW, Fonseca W. NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development. Viruses 2021; 13.
  3. Fonseca W, Malinczak CA, Fujimura K, Li D, McCauley K, Li J, Best SKK, Zhu D, Rasky AJ, Johnson CC, Bermick J, Zoratti EM, Ownby D, Lynch SV, Lukacs NW, Ptaschinski C. Maternal gut microbiome regulates immunity to RSV infection in offspring. The Journal of Experimental medicine 2021; 218.
  4. Fonseca W, Lukacs NW, Elesela S, Malinczak CA. Role of ILC2 in Viral-Induced Lung Pathogenesis. Frontiers in immunology 2021; 12: 675169.
  5. Schuler CFt, Malinczak CA, Best SKK, Morris SB, Rasky AJ, Ptaschinski C, Lukacs NW, Fonseca W. Inhibition of uric acid or IL-1beta ameliorates respiratory syncytial virus immunopathology and development of asthma. Allergy 2020; 75: 2279-2293.
  6. Malinczak CA, Fonseca W, Rasky AJ, Ptaschinski C, Morris S, Ziegler SF, Lukacs NW. Sex-associated TSLP-induced immune alterations following early-life RSV infection leads to enhanced allergic disease. Mucosal immunology 2019; 12: 969-979.