Editorial pubs.acs.org/journal/aidcbc
Taking Aim at Host−Pathogen Interactions
I
acsinfecdis.6b00161). To critically examine the molecular interactions between host and virus, reasonable models to study ZIKV replication and pathogenesis as well as immunological responses are needed. Progress on these fronts is discussed. Also presented are considerations for the development of emerging diagnostic tools, pharmacological inhibitor development, and prevention strategies through vaccine candidate development. An enabling factor to the discovery of new host−pathogen interactions comprises new and innovative tools and technologies. Two companion reviews in this issue by Strmiskova et al. (DOI: 10.1021/acsinfecdis.6b00084) and Kindrachuk and co-workers (DOI: 10.1021/acsinfecdis.6b00104) examine the roles of different -omics data derived from basic research methods such as chemical proteomics and kinome screens for the discovery of host−virus interactions. New and emerging methods such as these allow for the rapid discovery of new therapeutic targets and help to unravel the complexities of the interactions involved. Kindrachuk and coworkers look further into the value of integrating basic and clinical data to manage and treat current and emerging pathogens. Together, these reviews highlight the importance of the creation of new probes and assays for the genome-wide interrogation of host−virus interactions. Mycobacterium tuberculosis, first discovered by Robert Koch in 1882, is a bacterial pathogen that primarily infects the mammalian lung. It is a global health concern and one of the most studied infectious agents. In this issue, Bertozzi and coworkers uncover the biosynthesis and regulation of the metabolite sulfomenaquinone, a molecule with a role in the virulence of M. tuberculosis (DOI: 10.1021/acsinfecdis.6b00106). They show that this metabolite appears to play a negligible role in the growth or cell wall integrity of M. tuberculosis in vitro. Instead, an alternative hypothesis that it alters the ability of the host to control bacterial growth during the acute phase of infection is put forward. Bertozzi and coworkers present intriguing evidence that this metabolite could be blocking or altering the ability of macrophages to mount an effective response to M. tuberculosis. M. tuberculosis is known to propagate in highly oxygenated environments in the mammalian lung. In a companion study in this issue, Bogyo and coworkers report the design of substrates and activity-based probes for the virulence-dependent enzyme Hydrolase Important for Pathogenesis 1 (HIP1) from this pathogen (DOI: 10.1021/acsinfecdis.6b00092). Using this innovative approach, they discover pharmacophores with substituted 7amino-4-chloro-3-(2-bromoethoxy)isocoumarins as irreversible inhibitor scaffolds against HIP1. Furthermore, their team further optimized a selective chloroisocoumarin inhibitor. The new molecular probes for HIP1 represent new biotechnological tools that are not only useful in delineating the roles of HIP1
n the study of infectious diseases, the pathogen invades and establishes a biological foothold in another host organism, gaining significant energetic and replicative advantage while also causing negative repercussions such as illness and disease in the host. Generally, the first step in host−pathogen interactions starts at the point of entry into the host organism and ends at the final step of transmission. All steps in between involve biochemical interactions that, in part, benefit the pathogen through a gain in energy and resources and enable propagation. These molecular interactions also control cellular tropism/targeting and mechanisms by which the pathogen alters host cells and environment. Biomolecular warfare in the form of host cellular and immune responses to infection represents the countermeasures deployed by the host organism. The biological arms race between host and pathogen has evolved to incorporate elaborate evasion strategies by the pathogen in an effort to endure through time. This molecular interplay between host and pathogen also governs the severity and chronicity of infection. Thus, understanding the molecular basis for host−pathogen interactions not only helps us to uncover the nature of infection, but reveals the diagnostic and therapeutic targets required to combat infection and eradicate the pernicious infectious agents. In this special issue, we highlight different modern approaches toward the biochemical study of host−pathogen interactions and the insights and future directions that these approaches bring to combatting infectious diseases. One of the initial lines of defense in the battle between host and pathogen involves the innate immune system and the process of recognition of the pathogen as a deleterious entity. In this issue, Grimes (DOI: 10.1021/acsinfecdis.6b00174) discusses different receptors and mechanisms that have emerged recently as being involved in innate immune recognition; the importance of interdisciplinary teams in these discoveries is highlighted. In addition, a new hypothesis is put forward as to the definition of an innate immune receptor. Houghton and co-workers also review the structure and function of the hepatitis C virus (HCV) envelope glycoproteins (DOI: 10.1021/acsinfecdis.6b00110). Being critical for host cell recognition and entry by the virus makes these glycoproteins targets for therapeutic development and targets for the adaptive immune response. Recent structural data are discussed in these contexts and on binding sites of cross-neutralizing antibodies. The chemical interactions leading to heterodimerization, including the roles of transmembrane domains, disulfide bonding, and heptad repeat regions, are discussed as well as future strategies for the development of therapeutic and new vaccine candidates. Recently, the re-emergence of the Zika virus (ZIKV) has drawn much attention because of its links to human illness, especially during pregnancy. This re-emergence gained much attention because of its association with the 2016 summer Olympic games and concomitant global spread. In a comprehensive review, Richer, Sagan, and co-workers discuss the current state of research on ZIKV (DOI: 10.1021/ © 2016 American Chemical Society
Special Issue: Host-Pathogen Interactions Received: October 27, 2016 Published: November 11, 2016 744
DOI: 10.1021/acsinfecdis.6b00182 ACS Infect. Dis. 2016, 2, 744−745
ACS Infectious Diseases
Editorial
during pathogenesis of M. tuberculosis but also represent an important step in expanding the chemical toolbox for the study of mycobacterial proteases leading to new pharmacological inhibitors for therapeutic intervention. In this issue, Magistrado et al. report the study of resistance mechanisms to the novel antimalarial benzimidazolyl piperidine MMV007564 (DOI: 10.1021/acsinfecdis.6b00025). Resistance mutations mapped to a gene called Plasmodium falciparum cyclic amine resistance locus (pfcarl). They showed that mutations in pfcarl are strongly associated with resistance to a structurally unrelated imidazolopiperazines, currently in clinical trials. Their findings interestingly point to the gene pfcarl as being a multidrug-resistance gene with important implications in the therapeutic treatment of malaria. Also in this issue, Alkaitis and Ackerman report studies of tetrahydrobiopterin supplementation on malaria progression (DOI: 10.1021/ acsinfecdis.6b00124). They found that continuous infusion of sepiapterin, a tertrahydrobiopterin precursor, and citrulline, an arginine precursor, raised the concentrations of tertrahydrobiopterin and arginine in both blood and tissue compartments in a mouse model for severe malaria. However, the restoration of the levels of these important metabolites failed to prevent the onset of severe disease symptoms. Interestingly, they did observe that sepiapterin and citrulline infusion reduced the ratio of phenylalanine to tyrosine in plasma, aortic, and brain tissue. The authors hypothesize, on the basis of their reported findings, that sepiapterin treatment and the concomitant normalization of phenylalanine metabolism in patients with severe malaria may improve outcomes. Viruses such as HCV are obligate parasites, subverting their host cell machinery to propagate. One well-established targetable interaction is between the HCV protein NS5A and human protein cyclophilin A (CypA). In this issue, Götte and co-workers use mass spectrometry-based protein footprinting to characterize regions forming contacts between the disordered domain II of NS5A with various binding partners (DOI: 10.1021/acsinfecdis.6b00143). Interestingly, they characterize regions of interaction between NS5A and CypA that also overlap with regions that interact with other proteins and viral RNA and have studied the interactions of domain II of NS5A with unprecedented detail. HCV is also known to extensively remodel the host-cell endoplasmic reticulum (ER), creating virus-induced alterations to cellular membranes that are used for viral replication. Also examining NS5A, Barakat and colleagues investigated the mode of binding of direct acting antivirals (DOI: 10.1021/acsinfecdis.6b00113). Binding modes were characterized computationally showing how Daclatasvir and related molecules interact. The authors also explain how resistance mutations toward this class of compound arise. In an elegant study, Yang and co-workers show that membrane fluidity is affected by HCV-induced changes in the levels of the metabolite desmosterol (DOI: 10.1021/ acsinfecdis.6b00086). They used fluorescence recovery after photobleaching (FRAP) experiments on synthetic supported lipid bilayers to show desmosterol-induced increase in lipid bilayer fluidity. LC-MS characterization of desmosterol levels also showed that it is abundant in the membranes used by HCV to replicate in different models for HCV propagation. Altogether, their studies point to desmosterol as a fluiditypromoting metabolite, which when up-regulated by HCV contributes to the extensive membrane remodeling that takes place in the ER during HCV infection. Also in this issue, Lafreniere et al. show that HCV is sensitive to oxidative stress
and host-cell protein alkylation, particularly of host-cell chaperones, induced by the natural product 6-hydroxydopamine (DOI: 10.1021/acsinfecdis.6b00098). They developed a proteomic probe based on 6-hydroxydopamine to characterize the changes to the host-cell proteome that give rise to the antiviral effect. In terms of strategies for blocking host−pathogen interactions, none is more relevant than blocking cell entry. In a comprehensive study, Bewley and co-workers in this issue report on their findings pertaining to the binding site geometry and subdomain valency of neutralizing lectins on HIV-1 viral particles that prevent cell entry (DOI: 10.1021/acsinfecdis.6b00139). The authors studied the effects of lectins with different valencies, oligomerization states, and relative orientations of carbohydrate binding sites as inhibitors of HIV-1 viral entry. Carbohydrate binding site geometry and valency were found to be critical factors. Interestingly, surface plasmon resonance experiments also revealed secondary binding events only for lectins that could aggregate viral particles. The authors demonstrate elegantly how binding and aggregation phenomena may translate to neutralization potency and therapeutic potential. This special issue contains diverse examples of how chemistry/chemical biology approaches can be used to understand host−pathogen interactions. It is through these and other innovative strategies that we collectively learn about the fundamental nature of infection. This new knowledge then provides the basis for diagnostics, therapeutic strategies, and vaccine development. It is an exciting journey of discovery, enabled by new tools and technologies, with tremendous potential for societal impacts. It will also be exciting to see how these and other findings pertaining to host−pathogen interactions translate into effective methods to manage and even eradicate deleterious infectious diseases.
John Paul Pezacki,* Guest Editor
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Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie Private, Ottawa, Ontario, Canada K1N 6N5
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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DOI: 10.1021/acsinfecdis.6b00182 ACS Infect. Dis. 2016, 2, 744−745
