Overview of Infectious Diseases
Infectious diseases are caused by pathogenic microorganisms such as bacteria, viruses, fungi, and parasites. They spread through various means including direct contact, airborne transmission, ingestion of contaminated food or water, and vector-borne transmission. Despite advancements in medical science, infectious diseases continue to pose significant challenges, especially in regions with limited access to healthcare resources. Understanding the molecular mechanisms underlying pathogen-host interactions is essential for developing effective strategies for disease prevention, diagnosis, and treatment.
Glycans in Pathogen-Host Interactions
Adhesion and Invasion Mechanisms of Pathogens
Pathogens employ diverse strategies to adhere to and invade host cells, initiating the infectious process. Glycans serve as key mediators of these interactions, facilitating specific recognition and binding between pathogens and host cell surfaces. For instance, many bacterial pathogens express surface glycoproteins or lipopolysaccharides (LPS) decorated with glycan structures that enable them to adhere to host cell receptors, such as glycosaminoglycans (GAGs) or glycolipids.
Similarly, viruses exploit host cell glycans as attachment factors for viral entry. Viral envelope glycoproteins, such as the influenza virus hemagglutinin (HA) or the human immunodeficiency virus (HIV) envelope protein gp120, recognize and bind to specific glycan receptors on host cell surfaces, facilitating viral attachment and fusion with the host cell membrane.
Host Cell Recognition by Pathogens through Glycans
In addition to pathogen-derived glycans mediating adhesion to host cells, pathogens also recognize and exploit host cell glycans as receptors for adhesion and invasion. Host cell glycans, particularly those present on glycoproteins and glycolipids on the cell surface, serve as recognition sites for pathogen adhesion molecules. By targeting specific glycan structures on host cell surfaces, pathogens can efficiently adhere to and enter host cells, establishing infection within host tissues.
The specificity of pathogen-host interactions mediated by glycans is often determined by the unique repertoire of glycan structures present on host cell surfaces. Pathogens may exhibit preferential binding to certain glycan motifs or structures, allowing for selective recognition and targeting of host tissues conducive to infection.
Evasion of Host Immune Responses via Glycan Camouflage
Glycans not only facilitate pathogen adhesion and invasion but also play a crucial role in modulating host immune responses to infection. Pathogens have evolved sophisticated mechanisms to evade host immune surveillance by exploiting glycan camouflage. This involves decorating their surfaces with host-like glycans or modifying their own surface glycans to resemble host structures, thereby masking their identity and avoiding detection by the immune system.
By mimicking host glycans, pathogens can effectively "cloak" themselves from recognition by host immune cells and antibodies, enabling them to evade immune clearance and establish persistent infection. Additionally, pathogens may selectively modify their surface glycans to shield antigenic epitopes from immune recognition, further enhancing their ability to evade host immune responses and perpetuate infection.
Glycan interactions between host and virus (Miller et al., 2012).
Glycans as Diagnostic and Therapeutic Targets
Glycan Biomarkers for Infectious Diseases
Glycan alterations occur in response to infection, reflecting changes in cellular glycosylation patterns and host-pathogen interactions. These changes can serve as diagnostic biomarkers for infectious diseases, providing valuable information about disease presence, severity, and progression. For example, aberrant glycosylation of serum proteins or glycoproteins shed by infected cells may indicate the presence of infection and enable early disease detection.
In addition to systemic changes in glycan expression, pathogens themselves often exhibit unique glycan profiles that can be exploited for diagnostic purposes. Detection of pathogen-specific glycans in clinical samples, such as blood or urine, can provide direct evidence of infection and aid in identifying the causative agent. Moreover, glycan biomarkers may offer insights into disease prognosis and treatment response, enabling clinicians to tailor therapeutic strategies to individual patients' needs.
Development of Glycan-Based Diagnostic Tools
Advancements in glycomics technologies have revolutionized the field of infectious disease diagnostics, enabling the development of innovative glycan-based assays with enhanced sensitivity and specificity. Glycan microarrays, for example, allow for high-throughput screening of clinical samples to detect pathogen-specific glycan signatures indicative of infection. These platforms enable rapid and comprehensive profiling of glycan biomarkers, facilitating early disease detection and monitoring of disease progression.
Mass spectrometry-based glycoproteomics and glycan sequencing techniques provide complementary approaches for analyzing complex glycan structures in clinical samples. By identifying specific glycan motifs associated with infectious diseases, researchers can develop targeted diagnostic assays capable of distinguishing between different pathogens and disease states. Moreover, advances in glycan imaging technologies, such as lectin histochemistry and glycan-specific antibodies, enable visualization of glycan distributions in tissues, offering insights into disease pathogenesis and tissue tropism.
Targeting Glycans for Therapeutic Intervention
In addition to their diagnostic utility, glycans represent attractive targets for therapeutic intervention in infectious diseases. By disrupting key glycan-mediated interactions between pathogens and host cells, therapeutic agents can inhibit infection, reduce disease severity, and enhance host immune responses. Strategies such as glycan-based vaccines, glycan-binding antibodies, and glycosidase inhibitors hold promise for targeting specific glycan structures involved in pathogen adhesion, invasion, and immune evasion.
Glycan-based vaccines stimulate the immune system to produce antibodies that recognize and neutralize pathogen-specific glycans, thereby preventing infection or reducing disease severity upon subsequent exposure. Similarly, monoclonal antibodies targeting pathogen-derived glycans or glycan-binding lectins can block key steps in the infectious process, such as adhesion or entry into host cells. Furthermore, glycosidase inhibitors, which interfere with the enzymatic processing of glycans, may disrupt pathogen glycan biosynthesis or host glycan recognition, providing novel avenues for therapeutic intervention.
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Examples of Glycan Involvement in Specific Infectious Diseases
HIV/AIDS
Human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), exploits host cell glycans for viral entry, immune evasion, and antigenic variation. The viral envelope glycoprotein, gp120, interacts with host cell receptors, primarily CD4 and chemokine receptors, through specific glycan motifs. Glycan shielding of gp120 protects the virus from neutralizing antibodies and facilitates immune evasion, contributing to viral persistence and disease progression.
Furthermore, HIV hijacks host cell glycosylation machinery to modify its own glycan structures, creating a diverse array of viral glycoforms that evade immune detection and recognition. This glycan variability poses challenges for vaccine development and therapeutic targeting, as HIV continually evolves to escape immune surveillance. Understanding the complex interplay between viral and host glycans is critical for developing effective strategies to prevent HIV infection and manage AIDS.
Influenza
Influenza viruses, including seasonal flu strains and pandemic viruses such as H1N1 and H5N1, utilize host cell glycans for viral attachment, membrane fusion, and immune evasion. The viral surface glycoprotein, hemagglutinin (HA), recognizes sialic acid-containing glycans on host cell surfaces, facilitating viral entry and infection. Additionally, influenza viruses undergo antigenic drift and shift through glycan-mediated changes in viral glycoproteins, enabling evasion of host immune responses and emergence of novel strains with pandemic potential.
Glycans also play a role in modulating host immune responses to influenza infection. Sialylated glycans on respiratory epithelial cells serve as decoy receptors, preventing viral attachment to target cells and facilitating clearance of infected cells by mucosal immune defenses. However, influenza viruses can evolve to recognize alternative glycan receptors, allowing for continued replication and transmission within the host population.
Tuberculosis
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), employs complex glycan structures to modulate host immune responses and establish chronic infection. Surface-exposed glycolipids such as lipoarabinomannan (LAM) play crucial roles in mycobacterial virulence, immune evasion, and granuloma formation within host tissues. LAM interacts with host cell receptors and immune effectors, influencing cytokine production, phagocytosis, and antigen presentation.
M. tuberculosis alters host cell glycosylation patterns to subvert immune surveillance and promote intracellular survival. The bacterium induces the expression of specific glycosyltransferases and glycosidases in infected cells, leading to aberrant glycan modifications that impair immune recognition and clearance of the pathogen. Targeting mycobacterial glycans represents a promising approach for TB diagnosis, treatment, and vaccine development, offering new avenues for combating this global health threat.
Malaria
Glycans are intimately involved in various stages of the malaria parasite's life cycle, including host cell invasion, immune evasion, and pathogenesis. Plasmodium spp. express glycosylated proteins and lipids on their surfaces, which mediate interactions with host cell receptors and immune effectors. Glycan-mediated adhesion of infected red blood cells to endothelial receptors facilitates sequestration of parasites within host tissues, contributing to disease pathogenesis and organ dysfunction.
Glycans play a role in modulating host immune responses to malaria infection. Parasite-derived glycans, such as glycosylphosphatidylinositol (GPI) anchors and glycosylated antigens, elicit inflammatory cytokine production and immune cell activation, leading to tissue damage and systemic inflammation. Glycan-based vaccines and antimalarial drugs targeting parasite glycans show promise for malaria prevention and treatment, offering novel approaches to combat this deadly disease.
COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, exploits host cell glycans for viral entry, immune evasion, and pathogenesis. The viral spike glycoprotein, which facilitates viral attachment and entry into host cells, interacts with host cell surface receptors, primarily angiotensin-converting enzyme 2 (ACE2), through glycan-mediated interactions. SARS-CoV-2 utilizes host cell glycans as attachment factors for viral entry and as decoy receptors to evade immune surveillance.
Glycan shielding of viral spike glycoproteins protects SARS-CoV-2 from neutralizing antibodies and facilitates immune evasion, enabling viral persistence and dissemination within the host population. Understanding the role of glycans in SARS-CoV-2 infection is critical for developing effective therapeutics, vaccines, and diagnostic assays to combat the ongoing COVID-19 pandemic.
Reference
- Miller, Nathaniel L., et al. "Glycans in virus-host interactions: A structural perspective." Frontiers in Molecular Biosciences 8 (2021): 666756.