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Published on: January 21, 2018
Early-life heterologous rhinovirus infections induce an exaggerated asthma-like phenotype
Charu Rajput1, Mingyuan Han1, Tomoko Ishikawa1
1Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Mich.
Background:
Early-life wheezing-associated respiratory tract infection by rhinovirus (RV) is a risk factor for asthma development. Infants are infected with many different RV strains per year.
Objective:
We previously showed that RV infection of 6-day-old BALB/c mice induces a mucous metaplasia phenotype that is dependent on type 2 innate lymphoid cells (ILC2s). We hypothesized that early-life RV infection alters the response to subsequent heterologous infection, inducing an exaggerated asthma-like phenotype.
Methods:
Wild-type BALB/c mice and Rorafl/flIl7rcre mice lacking ILC2s were treated as follows: (1) sham on day 6 of life plus sham on day 13 of life, (2) RV-A1B on day 6 plus sham on day 13, (3) sham on day 6 plus RV-A2 on day 13, and (4) RV-A1B on day 6 plus RV-A2 on day 13.
Results:
Mice infected with RV-A1B at day 6 and sham at day 13 showed an increased number of bronchoalveolar lavage eosinophils and increased expression of IL-13 mRNA but not expression of IFN-γ mRNA (which is indicative of a type 2 immune response), whereas mice infected with sham on day 6 and RV-A2 on day 13 of life demonstrated increased IFN-γ expression (which is a mature antiviral response). In contrast, mice infected with RV-A1B on day 6 before RV-A2 infection on day 13 showed increased expression of IL-13, IL-5, Gob5, Muc5b, and Muc5ac mRNA; increased numbers of eosinophils and IL-13-producing ILC2s; and exaggerated mucus metaplasia and airway hyperresponsiveness. Compared with Rorafl/fl mice, Rorafl/flIl7rcre mice showed complete suppression of bronchoalveolar lavage eosinophils and mucous metaplasia.
Conclusion:
Early-life RV infection alters the response to subsequent heterologous infection, inducing an intensified asthma-like phenotype that is dependent on ILC2s.
Insights
Early rhinovirus (RV) infection in infants primes the immune system, leading to an exaggerated asthma-like response upon subsequent infections. This heightened allergic reaction is dependent on type 2 innate lymphoid cells (ILC2s).
Area of Science:
- Immunology
- Respiratory Medicine
- Pediatrics
Background:
- Early-life respiratory tract infections, particularly by rhinovirus (RV), are significant risk factors for asthma development.
- Infants are frequently exposed to diverse RV strains annually, increasing susceptibility.
- Previous research linked RV infection in young mice to mucous metaplasia, a process mediated by type 2 innate lymphoid cells (ILC2s).
Purpose of the Study:
- To investigate whether early-life RV infection modifies the immune response to subsequent, different RV infections.
- To determine if this altered response leads to an exaggerated asthma-like phenotype.
- To elucidate the role of ILC2s in mediating these changes.
Main Methods:
- BALB/c mice (wild-type and ILC2-deficient Rorafl/flIl7rcre) were subjected to sequential infections with different RV strains (RV-A1B and RV-A2) or sham treatments at specific early-life time points.
- Mice received either sham or RV-A1B on day 6, followed by sham or RV-A2 on day 13.
- Immune responses, including bronchoalveolar lavage eosinophils, cytokine mRNA expression (IL-13, IFN-γ), mucus production markers (Gob5, Muc5b, Muc5ac), and airway hyperresponsiveness, were assessed.
Main Results:
- Single RV-A1B infection in early life induced a type 2 immune response (increased IL-13), while RV-A2 induced a type 1 response (increased IFN-γ).
- Sequential infection (RV-A1B followed by RV-A2) resulted in significantly amplified type 2 responses, characterized by elevated IL-13, IL-5, mucus production, eosinophils, and ILC2s.
- This sequential infection led to exaggerated mucus metaplasia and airway hyperresponsiveness, mimicking asthma.
- ILC2-deficient mice showed a complete absence of these exaggerated responses, confirming ILC2 dependence.
Conclusions:
- Early-life RV infection profoundly alters the immune system's response to subsequent heterologous infections.
- This alteration results in an intensified, asthma-like phenotype.
- The development of this exaggerated phenotype is critically dependent on the presence and function of ILC2s.
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