Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies.

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. Thus, the virus-host interactions and conflicts, as well as the ability to govern biological events at this first line of defense, contribute significantly to the pathogenesis and outcomes of EV-A71 infection. In this review, we update recent progress on host innate immune responses to EV-A71 infection. In addition, we discuss the underlying strategies employed by EV-A71 to escape host innate immune responses. A better understanding of the interplay between EV-A71 and host innate immunity may unravel potential antiviral targets, as well as strategies that can improve patient outcomes.

Intertwined: SAMHD1 cellular functions, restriction, and viral evasion strategies.

SAMHD1 was initially described for its ability to efficiently restrict HIV-1 replication in myeloid cells and resting CD4+ T cells. However, a growing body of evidence suggests that SAMHD1-mediated restriction is by far not limited to lentiviruses, but seems to be a general concept that applies to most retroviruses and at least a number of DNA viruses. SAMHD1 anti-viral activity was long believed to be solely due to its ability to deplete cellular dNTPs by enzymatic degradation. However, since its discovery, several new functions have been attributed to SAMHD1. It has been demonstrated to bind nucleic acids, to modulate innate immunity, as well as to participate in the DNA damage response and resolution of stalled replication forks. Consequently, it is likely that SAMHD1-mediated anti-viral activity is not or not exclusively mediated through its dNTPase activity. Therefore, in this review, we summarize current knowledge on SAMHD1 cellular functions and systematically discuss how these functions could contribute to the restriction of a broad range of viruses besides retroviruses: herpesviruses, poxviruses and hepatitis B virus. Furthermore, we aim to highlight different ways how viruses counteract SAMHD1-mediated restriction to bypass the SAMHD1-mediated block to viral infection.

Beyond traditional medications: exploring novel and potential inhibitors of trypanothione reductase (LmTr) of Leishmania parasites.

The trypanothione reductase enzyme, which neutralizes the reactive oxygen species produced inside the macrophages to kill the parasites, is one of the evasion strategies Leishmania uses to survive inside the cells. The vitality of the parasite depends on Leishmania major trypanothione reductase (LmTr), a NADPH-dependent flavoprotein oxidoreductase essential for thiol metabolism. Since this enzyme is distinct and lacking in humans, we focused on it in our study to screen for new inhibitors to combat leishmaniasis. Using the I-TASSER server, a three-dimensional model of LmTr was generated. The Autodock vina program was used in high-throughput virtual screening of the ZINC database. The top seven molecules were ranked according to their binding affinity. The compounds with the highest binding affinities and the right number of hydrogen bonds were chosen. These compounds may be effective at inhibiting the target enzyme's (LmTr) activity, making them new leishmaniasis treatments. These compounds may serve as a useful starting point for a hit-to-lead approach in the quest for new anti-Leishmania drugs that are more efficient and less cytotoxic. The average node degree is 5.09, the average local clustering coefficient is 0.868, and the PPI enrichment p-value is 8.9e-06, indicating that it is sufficiently connected to regulate the network. TRYR (LmTr protein) also interacts physically with ten additional proteins in the pathogenesis network. The findings of the study indicated that successfully suppressing the LmTr protein in vitro and in vivo may finally result in regulating the L. major pathogenesis.Communicated by Ramaswamy H. Sarma.

Macrophage Mediated Immunomodulation During Cryptococcus Pulmonary Infection.

Macrophages are key cellular components of innate immunity, acting as the first line of defense against pathogens to modulate homeostatic and inflammatory responses. They help clear pathogens and shape the T-cell response through the production of cytokines and chemokines. The facultative intracellular fungal pathogen Cryptococcus neoformans has developed a unique ability to interact with and manipulate host macrophages. These interactions dictate how Cryptococcus infection can remain latent or how dissemination within the host is achieved. In addition, differences in the activities of macrophages have been correlated with differential susceptibilities of hosts to Cryptococcus infection, highlighting the importance of macrophages in determining disease outcomes. There is now abundant information on the interaction between Cryptococcus and macrophages. In this review we discuss recent advances regarding macrophage origin, polarization, activation, and effector functions during Cryptococcus infection. The importance of these strategies in pathogenesis and the potential of immunotherapy for cryptococcosis treatment is also discussed.

Hide-and-Seek: A Game Played between Parasitic Protists and Their Hosts.

After invading the host organism, a battle occurs between the parasitic protists and the host's immune system, the result of which determines not only whether and how well the host survives and recovers, but also the fate of the parasite itself. The exact weaponry of this battle depends, among others, on the parasite localisation. While some parasitic protists do not invade the host cell at all (extracellular parasites), others have developed successful intracellular lifestyles (intracellular parasites) or attack only the surface of the host cell (epicellular parasites). Epicellular and intracellular protist parasites have developed various mechanisms to hijack host cell functions to escape cellular defences and immune responses, and, finally, to gain access to host nutrients. They use various evasion tactics to secure the tight contact with the host cell and the direct nutrient supply. This review focuses on the adaptations and evasion strategies of parasitic protists on the example of two very successful parasites of medical significance, Cryptosporidium and Leishmania, while discussing different localisation (epicellular vs. intracellular) with respect to the host cell.

Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across.

The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA's innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.

Cell-Mediated Responses to Human Metapneumovirus Infection.

Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.

Sensor Sensibility-HIV-1 and the Innate Immune Response.

Innate immunity represents the human immune system's first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) is a unique human RNA virus that causes acquired immunodeficiency syndrome (AIDS) in infected individuals. During the replication cycle, HIV-1 undergoes reverse transcription of its RNA genome and integrates the resulting DNA into the human genome. Subsequently, transcription of the integrated provirus results in production of new virions and spreading infection of the virus. Throughout the viral replication cycle, numerous nucleic acid derived PAMPs can be recognized by a diverse set of innate immune sensors in infected cells. However, HIV-1 has evolved efficient strategies to evade or counteract this immune surveillance and the downstream responses. Understanding the molecular underpinnings of the concerted actions of the innate immune system, as well as the corresponding viral evasion mechanisms during infection, is critical to understanding HIV-1 transmission and pathogenesis, and may provide important guidance for the design of appropriate adjuvant and vaccine strategies. Here, we summarize current knowledge of the molecular basis for sensing HIV-1 in human cells, including CD4+ T cells, dendritic cells, and macrophages. Furthermore, we discuss the underlying mechanisms by which innate sensing is regulated, and describe the strategies developed by HIV-1 to evade sensing and immune responses.

In the Crosshairs: RNA Viruses OR Complement?

Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible "hijacking" of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus-complement interactions.

Helicobacter pylori evasion strategies of the host innate and adaptive immune responses to survive and develop gastrointestinal diseases.

Helicobacter pylori (H. pylori) is a bacterial pathogen that resides in more than half of the human population and has co-evolved with humans for more than 58,000 years. This bacterium is orally transmitted during childhood and is a key cause of chronic gastritis, peptic ulcers and two malignant cancers including MALT (mucosa-associated lymphoid tissue) lymphoma and adenocarcinoma. Despite the strong innate and adaptive immune responses, H. pylori has a long-term survival in the gastric mucosa. In addition to the virulence factors, survival of H. pylori is strongly influenced by the ability of bacteria to escape, disrupt and manipulate the host immune system. This bacterium can escape from recognition by innate immune receptors via altering its surface molecules. Moreover, H. pylori subverts adaptive immune response by modulation of effector T cell. In this review, we discuss the immune-pathogenicity of H. pylori by focusing on its ability to manipulate the innate and acquired immune responses to increase its survival in the gastric mucosa, leading up to gastrointestinal disorders. We also highlight the mechanisms that resulted to the persistence of H. pylori in gastric mucosa.

Activation and counteraction of antiviral innate immunity by KSHV: an Update.

The innate immune responses triggering production of type I interferons and inflammatory cytokines constitute a nonspecific innate resistance that eliminates invading pathogens including viruses. The activation of innate immune signaling through pattern recognition receptors (PRRs) is by sensing pathogen-associated molecular patterns derived from viruses. According to their distribution within cells, PRRs are classified into three types of receptors: membrane, cytoplasmic, and nuclear. Kaposi's sarcoma-associated herpesvirus (KSHV), a large DNA virus, replicates in the nucleus. Its genome is protected by capsid proteins during transport in the cytosol. Multiple PRRs are involved in KSHV recognition. To successfully establish latent infection, KSHV has evolved to manipulate different aspects of the host antiviral innate immune responses. This review presents recent advances in our understanding about the activation of the innate immune signaling in response to infection of KSHV. It also reviews the evasion strategies used by KSHV to subvert host innate immune detection for establishing a persistent infection.

The Ebola-Glycoprotein Modulates the Function of Natural Killer Cells.

The Ebola virus (EBOV) uses evasion mechanisms that directly interfere with host T-cell antiviral responses. By steric shielding of human leukocyte antigen class-1, the Ebola glycoprotein (GP) blocks interaction with T-cell receptors (TCRs), thus rendering T cells unable to attack virus-infected cells. It is likely that this mechanism could promote increased natural killer (NK) cell activity against GP-expressing cells by preventing the engagement of NK inhibitory receptors; however, we found that primary human NK cells were less reactive to GP-expressing HEK293T cells. This was manifested as reduced cytokine secretion, a reduction in NK degranulation, and decreased lysis of GP-expressing target cells. We also demonstrated reduced recognition of GP-expressing cells by recombinant NKG2D and NKp30 receptors. In accordance, we showed a reduced monoclonal antibody-based staining of NKG2D and NKp30 ligands on GP-expressing target cells. Trypsin digestion of the membrane-associated GP led to a recovery of the recognition of membrane-associated NKG2D and NKp30 ligands. We further showed that membrane-associated GP did not shield recognition by KIR2DL receptors; in accordance, GP expression by target cells significantly perturbed signal transduction through activating, but not through inhibitory, receptors. Our results suggest a novel evasion mechanism employed by the EBOV to specifically avoid the NK cell immune response.

Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1).

Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4+ T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B. abortus is able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated that B. abortus infection inhibits the IFN-γ-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as B. abortus infection. IL-6 contributes to these down-regulatory phenomena. In addition, B. abortus and its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-γ signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection.

The in Vitro Inhibitory Effect of Ectromelia Virus Infection on Innate and Adaptive Immune Properties of GM-CSF-Derived Bone Marrow Cells Is Mouse Strain-Independent.

Ectromelia virus (ECTV) belongs to the Orthopoxvirus genus of the Poxviridae family and is a natural pathogen of mice. Certain strains of mice are highly susceptible to ECTV infection and develop mousepox, a lethal disease similar to smallpox of humans caused by variola virus. Currently, the mousepox model is one of the available small animal models for investigating pathogenesis of generalized viral infections. Resistance and susceptibility to ECTV infection in mice are controlled by many genetic factors and are associated with multiple mechanisms of immune response, including preferential polarization of T helper (Th) immune response toward Th1 (protective) or Th2 (non-protective) profile. We hypothesized that viral-induced inhibitory effects on immune properties of conventional dendritic cells (cDCs) are more pronounced in ECTV-susceptible than in resistant mouse strains. To this extent, we confronted the cDCs from resistant (C57BL/6) and susceptible (BALB/c) mice with ECTV, regarding their reactivity and potential to drive T cell responses following infection. Our results showed that in vitro infection of granulocyte-macrophage colony-stimulating factor-derived bone marrow cells (GM-BM-comprised of cDCs and macrophages) from C57BL/6 and BALB/c mice similarly down-regulated multiple genes engaged in DC innate and adaptive immune functions, including antigen uptake, processing and presentation, chemokines and cytokines synthesis, and signal transduction. On the contrary, ECTV infection up-regulated Il10 in GM-BM derived from both strains of mice. Moreover, ECTV similarly inhibited surface expression of major histocompatibility complex and costimulatory molecules on GM-BM, explaining the inability of the cells to attain full maturation after Toll-like receptor (TLR)4 agonist treatment. Additionally, cells from both strains of mice failed to produce cytokines and chemokines engaged in T cell priming and Th1/Th2 polarization after TLR4 stimulation. These data strongly suggest that in vitro modulation of GM-BM innate and adaptive immune functions by ECTV occurs irrespective of whether the mouse strain is susceptible or resistant to infection. Moreover, ECTV limits the GM-BM (including cDCs) capacity to stimulate protective Th1 immune response. We cannot exclude that this may be an important factor in the generation of non-protective Th2 immune response in susceptible BALB/c mice in vivo.

Evasion and Immuno-Endocrine Regulation in Parasite Infection: Two Sides of the Same Coin in Chagas Disease?

Chagas disease is a serious illness caused by the protozoan parasite Trypanosoma cruzi. Nearly 30% of chronically infected people develop cardiac, digestive, or mixed alterations, suggesting a broad range of host-parasite interactions that finally impact upon chronic disease outcome. The ability of T. cruzi to persist and cause pathology seems to depend on diverse factors like T. cruzi strains, the infective load and the route of infection, presence of virulence factors, the parasite capacity to avoid protective immune response, the strength and type of host defense mechanisms and the genetic background of the host. The host-parasite interaction is subject to a constant neuro-endocrine regulation that is thought to influence the adaptive immune system, and as the infection proceeds it can lead to a broad range of outcomes, ranging from pathogen elimination to its continued persistence in the host. In this context, T. cruzi evasion strategies and host defense mechanisms can be envisioned as two sides of the same coin, influencing parasite persistence and different outcomes observed in Chagas disease. Understanding how T. cruzi evade host's innate and adaptive immune response will provide important clues to better dissect mechanisms underlying the pathophysiology of Chagas disease.

Immune Escape Strategies of Malaria Parasites.

Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins, and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.

KSHV strategies for host dsDNA sensing machinery.

The innate immune system utilizes pattern recognition receptors cyclic GMP-AMP synthase (cGAS) to sense cytosolic double-stranded (ds) DNA and initiate type 1 interferon signaling and autophagy pathway, which collaborate to limit pathogen infections as well as alarm the adaptive immune response. The genomes of herpesviruses are large dsDNA, which represent a major class of pathogen signatures recognized by cellular DNA sensor cGAS. However, to successfully establish the persistent infection, herpesviruses have evolved their viral genes to modulate different aspects of host immune signaling. This review summarizes the evasion strategies of host cGAS DNA sensing pathway by Kaposi's Sarcoma-associated Herpesvirus (KSHV) and their contributions to KSHV life cycles.

More than just immune evasion: Hijacking complement by Plasmodium falciparum.

Malaria remains one of the world's deadliest diseases. Plasmodium falciparum is responsible for the most severe and lethal form of human malaria. P. falciparum's life cycle involves two obligate hosts: human and mosquito. From initial entry into these hosts, malaria parasites face the onslaught of the first line of host defence, the complement system. In this review, we discuss the complex interaction between complement and malaria infection in terms of hosts immune responses, parasite survival and pathogenesis of severe forms of malaria. We will focus on the role of complement receptor 1 and its associated polymorphisms in malaria immune complex clearance, as a mediator of parasite rosetting and as an entry receptor for P. falciparum invasion. Complement evasion strategies of P. falciparum parasites will also be highlighted. The sexual forms of the malaria parasites recruit the soluble human complement regulator Factor H to evade complement-mediated killing within the mosquito host. A novel evasion strategy is the deployment of parasite organelles to divert complement attack from infective blood stage parasites. Finally we outline the future challenge to understand the implications of these exploitation mechanisms in the interplay between successful infection of the host and pathogenesis observed in severe malaria.

Host-pathogen interactions between the human innate immune system and Candida albicans-understanding and modeling defense and evasion strategies.

The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.