Microbial immune evasion can be achieved through the expression, or mimicry, of host-like carbohydrates on the microbial cell surface to hide from detection. However, disparate reports collectively suggest that evasion could also be accomplished through the modulation of the host glycosylation pathways, a mechanism that we call the "Glyco-Evasion Hypothesis". Here, we will summarize the evidence in support of this paradigm by reviewing three separate bodies of work present in the literature. We review how infection and inflammation can lead to host glycosylation changes, how host glycosylation changes can increase susceptibility to infection and inflammation and how glycosylation impacts molecular and cellular function. Then, using these data as a foundation, we propose a unifying hypothesis in which microbial products can hijack host glycosylation to manipulate the immune response to the advantage of the pathogen. This model reveals areas of research that we believe could significantly improve our fight against infectious disease.
Studies centered on understanding how molecular structure affects biological function have historically focused on proteins. Circular dichroism (CD) is commonly used to analyze protein secondary structure, yet its application to other molecules is far less explored. In fact, little is known about how glycan conformation might affect function, likely because of a lack of tools for measuring dynamic structural changes of carbohydrates. In the present study, we developed a method based on CD to monitor conformational changes in the zwitterionic T-cell-activating glycoantigen polysaccharide A1 (PSA). We found that PSA helical structure produces a CD spectrum that is strikingly similar to proteins rich in alpha-helical content and is equally sensitive to nonpolar solvents. Like conventional T-cell-dependent proteins, PSA requires processing before major histocompatibility complex class II (MHCII) binding. CD spectra of PSA fragments of varying sizes indicated that fragments smaller than three repeating units lack helical content and are incapable of MHCII binding. Likewise, neutralization of charged groups in the repeating unit resulted in major conformational changes as measured by CD, which correlated with a lack of MHCII presentation. These data represent two significant findings: CD can be used to measure conformational changes in carbohydrates and the functional epitope from PSA is dependent on a specific conformation that is stabilized by adjacent repeating units and a zwitterionic charge motif. As a result, this work demonstrates that CD is a valuable tool for use in functional glycomics efforts that seek to align chemical and conformational structure with biological activity.
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