Science
IMMUNOLOGYA Decorated Virus Cannot Hide
+Author Affiliations
- E-mail: rherzog@ufl.edu; ostroda@pathology.ufl.edu
The innate immune system has many sensors for pathogens. For example, toll-like receptors (TLRs) on the surface of or inside cells recognize pathogen-associated molecular patterns typical for macromolecular structures of bacteria and viruses (4). Pattern recognition prompts the TLR to send a “danger” signal to the immune system (5). One of these receptors, TLR4, binds to components of bacterial cell walls such as lipopolysaccharide (LPS), although nonbacterial structures are also ligands for TLR4 (6).The coagulation system protects our bodies from excessive loss of blood from a leaky or damaged vessel, whereas the immune system protects us from invading pathogens such as viruses. Unexpected links between these two systems suggest their coevolution (1, 2). On page 795 in this issue, Doronin et al.show that an essential protein for the clotting process binds to a virus that has entered the blood stream, thereby allowing the immune system to sense the invader and mount a rapid and potent antiviral response (3).
Doronin et al. investigated the innate immune response to human adenovirus (HAdv), which causes the common cold. After entry of the virus into the blood, coagulation factor X (FX) binds to the hexon structure of the adenoviral protein capsid (3, 7, 8). FX is a serine protease that circulates as an inactive zymogen and, upon activation, is a critical component of the coagulation cascade (9). FX interaction with the viral capsid allows the virus to infect cells, such as hepatocytes, through cell surface receptors. Doronin et al. now show that immune cells (macrophages) sense FX-coated virus by way of TLR4 (see the figure).
Whereas other cell surface proteins may mediate cellular entry of adenovirus, interaction of the virus with TLR4 instead elicits intracellular signaling events that switch on production of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and monocyte chemotactic protein–1 (MCP1). These factors attract other inflammatory cells, thereby rapidly initiating a line of defense against the viral pathogen. Doronin et al. show that after TLR4 (expressed by macrophages) binds to an FX-coated adenovirus particle, it activates the transcription of proinflammatory cytokine genes through a signaling pathway that involves the intracellular adaptor molecules MyD88 and Toll–IL-1 receptor domain–containing adaptor inducing interferon-β (TRIF), and the transcription factor nuclear factor κB (NF-κB). Mutated adenovirus that cannot bind FX failed to produce this response. Thus, a component of the blood coagulation cascade enables the immune system to directly recognize a viral pathogen as opposed to exerting more general effects on inflammation or responding to components that may have been shed by pathogens or infected tissues. Other cytokine responses to adenovirus (such as IL-1α) are induced when the viral particle binds to integrin 3 on the surface of macrophages. Integrin 3 binds to the virus independently of FX or TLR but fails to trigger the full immune response to the virus (10). Indeed, Doronin et al. observed that TLR4-deficient mice were much less capable of clearing adenovirus than their wild-type counterparts.
Coated for binding.
Upon entry into the blood, human adenovirus serotype 5 (HAdv5) is bound by blood clotting factor X (FX). After translocation to tissues, such as liver or spleen, resident macrophages sense the FX-bound virus through TLR4, which activates the innate immune mechanism against the virus (required for a potent antiviral response).
CREDIT: Y. HAMMOND/SCIENCE
The activation mechanism of innate immunity identified by Doronin et al. is similar to aspects of adaptive immune responses. FX binding to viruses is reminiscent of antibody opsonization in which a pathogen is marked for ingestion and destruction by phagocytic cells bearing Fc receptors that recognize the antibody. FX is a “self” protein that is not immunogenic, but can elicit immune responses when bound to a carrier, such as adenovirus. Doronin et al. suggest that TLR4 recognizes the self-protein FX and binds directly to the FX-hexon complex. There is precedent for TLR4 recognition of a self-protein. Crystal structures demonstrate that TLR4 and the self-protein MD-2 (lymphocyte antigen 96) form a heterodimer that recognizes LPS from Gram-negative bacteria (11). MD-2 binds to concave surfaces of the horseshoe-shaped TLR4 and to LPS moieties, thus stimulating innate proinflammatory immune responses. The findings of Doronin et al. suggest a model in which FX functions in a manner analogous to MD-2 in facilitating specific binding through TLR4. HAdv5 binds to a key position on the surface of FX, resulting in the formation of a pattern established by the symmetry of the virus. Because FX and MD-2 have similar size and shape, FX may bind the concave surface of TLR4 that MD-2 contacts when binding LPS. Similarly, hemozoin, a disposal product of blood-feeding malaria parasites, activates TLR4 signaling when bound to fibrinogen (another coagulation factor), thereby contributing to induction of tumor necrosis factor (TNF) and MCP-1 expression (12).
The observation that self-proteins facilitate recognition of foreign pathogens by the innate immune system has implications for understanding the evolution of the adaptive immune system. Alternative recognition mechanisms in innate immunity, such as those mediated by FX and MD-2, could have served as early precedents to the more complex mechanisms of cellular immunity whereby peptide antigens are “presented” to T cells by self–major histocompatibility complex molecules.
Development of recombinant adenoviral vectors for human gene therapy has somewhat fallen out of favor over the past decade, but has shown recent promise for vaccination and cancer therapies (13,14). Analysis of the death of a patient in a clinical trial on hepatic delivery of recombinant adenovirus in 1999, and subsequent studies, documented the very strong and multifaceted innate immune response that can occur. Activation of multiple cell types and toxicities contribute (15). The adenoviral capsid and genome are detected by many different receptors, such as TLR2 and TLR9, inflammasomes (multiprotein structures that activate the inflammatory responses), and cytosolic DNA sensors, among others. Doronin et al. specifically investigated very early steps in the innate immune response in mice, which requires FX binding to TLR4 and subsequent TLR4 signaling for effective and rapid clearance of virus. But multiple additional mechanisms direct other steps of antiviral immunity. Thus, although adenoviral vectors are excellent models to study antiviral innate immunity, their “deimmunization” for treatment of genetic disease likely remains a challenge.
No comments:
Post a Comment