Rare Childhood Disorder Enhances Understanding of Resistance to Viral Infections

Sergio D. Rosenzweig, MD, PhD Director, Primary Immunodeficiency Clinic (PID-C) LHD, NIAID, NIH Head of the Infectious Diseases Susceptibility Unit at the Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD, 20892MedicalResearch.com Interview with:
Sergio D. Rosenzweig, MD, PhD
Director, Primary Immunodeficiency Clinic (PID-C)
Head of the Infectious Diseases Susceptibility Unit at the Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases National Institutes of Health
Bethesda, MD, 20892

MedicalResearch.com: What are the main findings of the study?

Dr. Rosenzweig: We diagnosed a disease called CDG-IIb in two siblings with severe development issues and very low levels of immunoglobulins, which include infection-fighting antibodies. These children were referred to the NIAID Primary Immunodeficiency Clinic through the NIH Undiagnosed Diseases Program. CDG-IIb is an extremely rare congenital disorder of glycosylation (CDG), with only one other case reported. The genetic defect of the disease disrupts glycosylation, the process for attaching and trimming sugars from proteins. Almost 50% of our proteins have sugars attached, and these are called glycoproteins. They include immunoglobulins and also some viral glycoproteins that are made when cells are infected by a virus. The spread of some viruses, including HIV and influenza, depend on viral glycoproteins in order to infect additional cells and form viral protective shields. We found that this type of virus was less able to replicate, infect other cells, or create adequate protective shields in CDG-IIb patient cells because of the glycosylation defect. In comparison, adenovirus, poliovirus, and vaccinia virus, which either do not rely on glycosylation or do not form protective glycoprotein shields, replicated normally when added to both CDG-IIb and healthy cells.

MedicalResearch.com: Were any of the findings unexpected?

Dr. Rosenzweig: While most of our patients’ clinical manifestation fit into what would be expected in patients with CDGs, the fact that they also presented with severe hypogammaglobulinemia (low levels of immunoglobulins) but did not have increased rates of infections was paradoxical, because patients with severe hypogammaglobulinemia typically have recurrent and severe bacterial and viral infections.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Rosenzweig: There are 3 major lessons we learned from these patients:

First, they taught us that hypogammaglobulinemia not only could arise from production defects (T and B cell disorders), or loss of immunoglobulins through stools and urine, but also due to intrinsic immunoglobulin defects related to the glycosylation pattern, which in turn determines the half life, or stability, of these molecules.

Second, and perhaps the most important lesson we learned, is that we may potentially treat individuals with molecules that modify glycosylation, and this may afford protection against infection from glycosylation-dependent viruses.

Last, but not least, these children reinforce the concept that by taking care of patients with very rare diseases, we can learn about basic mechanisms that not only help us to understand their uncommon diseases but can be generalized and extended for the benefit of the rest of the population.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Rosenzweig: We are exploring the possibility of using drugs that modify glycosylation to prevent and treat certain viral infections that depend on glycoproteins for the infection to spread. Besides HIV and influenza, which we already show in our work, other candidates may be dengue, respiratory syncytial virus (RSV) or even ebola virus, all microorganisms with very important clinical and epidemiological impacts.

 

Citation:
Brief Report: Glycosylation, Hypogammaglobulinemia, and Resistance to Viral Infections

M.A. Sadat and Others
NEJM Published Online: April 9, 2014

 

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