cGMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) sensing has emerged as a key regulator of innate immune responses to both exogenous and endogenous DNA. Recent studies reveal critical ...roles for this pathway in natural antitumor immunity across cancer types as well as in immune checkpoint blockade therapy. However, it is also clear that some tumors evade cGAS–STING-mediated immune responses, and immunomodulatory therapeutics are currently being explored to target this pathway. Finally, we also discuss recent observations that cGAS–STING-mediated inflammation may promote tumor initiation, growth, and metastasis in certain malignancies and how this may complicate the utility of this pathway in therapeutic development.
cGMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) recognizes cytosolic DNA and induces a type I interferon response in both tumor and phagocytic immune cells.
cGAS–STING-induced immunity has potent antitumor effects and magnifies the effects of a variety of anticancer therapeutics.
In certain tumor types, cGAS–STING promotes cancer growth and metastasis through modulation of the tumor microenvironment.
Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a regulator of several physiological processes. ACE2 has recently been ...proposed to be interferon (IFN) inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of IFN treatment in coronavirus disease 2019. Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a new isoform of ACE2, generated by co-option of intronic retroelements as promoter and alternative exon. The new transcript, termed MIRb-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and is highly responsive to IFN stimulation. In contrast, canonical ACE2 expression is unresponsive to IFN stimulation. Moreover, the MIRb-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and is therefore unlikely to contribute to or enhance viral infection.
We have previously described a novel temporal encoding mechanism in the somatosensory system, where mechanical pulses grouped into periodic bursts create a perceived tactile frequency based on the ...duration of the silent gap between bursts, rather than the mean rate or the periodicity. This coding strategy may offer new opportunities for transmitting information to the brain using various sensory neural prostheses and haptic interfaces. However, it was not known whether the same coding mechanisms apply when using electrical stimulation, which recruits a different spectrum of afferents. Here, we demonstrate that the predictions of the burst gap coding model for frequency perception apply to burst stimuli delivered with electrical pulses, re-emphasising the importance of the temporal structure of spike patterns in neural processing and perception of tactile stimuli. Reciprocally, the electrical stimulation data confirm that the results observed with mechanical stimulation do indeed depend on neural processing mechanisms in the central nervous system, and are not due to skin mechanical factors and resulting patterns of afferent activation.
Abstract
When tactile afferents were manipulated to fire in periodic bursts of spikes, we discovered that the perceived pitch corresponded to the inter-burst interval (burst gap) in a spike train, ...rather than the spike rate or burst periodicity as previously thought. Given that tactile frequency mechanisms have many analogies to audition, and indications that temporal frequency channels are linked across the two modalities, we investigated whether there is burst gap temporal encoding in the auditory system. To link this putative neural code to perception, human subjects (n = 13, 6 females) assessed pitch elicited by trains of temporally-structured acoustic pulses in psychophysical experiments. Each pulse was designed to excite a fixed population of cochlear neurons, precluding place of excitation cues, and to elicit desired temporal spike trains in activated afferents. We tested periodicities up to 150 Hz using a variety of burst patterns and found striking deviations from periodicity-predicted pitch. Like the tactile system, the duration of the silent gap between successive bursts of neural activity best predicted perceived pitch, emphasising the role of peripheral temporal coding in shaping pitch. This suggests that temporal patterning of stimulus pulses in cochlear implant users might improve pitch perception.
Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is ...an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, antitumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C -expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.
This study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies.
Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with ...the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.
Plasmodium vivax merozoites only invade reticulocytes, a minor though heterogeneous population of red blood cell precursors that can be graded by levels of transferrin receptor (CD71) expression. The ...development of a protocol that allows sorting reticulocytes into defined developmental stages and a robust ex vivo P vivax invasion assay has made it possible for the first time to investigate the fine-scale invasion preference of P vivax merozoites. Surprisingly, it was the immature reticulocytes (CD71+) that are generally restricted to the bone marrow that were preferentially invaded, whereas older reticulocytes (CD71−), principally found in the peripheral blood, were rarely invaded. Invasion assays based on the CD71+ reticulocyte fraction revealed substantial postinvasion modification. Thus, 3 to 6 hours after invasion, the initially biomechanically rigid CD71+ reticulocytes convert into a highly deformable CD71− infected red blood cell devoid of host reticular matter, a process that normally spans 24 hours for uninfected reticulocytes. Concurrent with these changes, clathrin pits disappear by 3 hours postinvasion, replaced by distinctive caveolae nanostructures. These 2 hitherto unsuspected features of P vivax invasion, a narrow preference for immature reticulocytes and a rapid remodeling of the host cell, provide important insights pertinent to the pathobiology of the P vivax infection.
•Plasmodium vivax merozoites preferentially infect a subgroup of reticulocytes generally restricted to the bone marrow.•Accelerated “maturation” of infected reticulocytes.
Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral ...immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.
PIWI-interacting RNAs (piRNAs) are emerging players in cancer genomics. Originally described in the germline, there are over 20,000 piRNA genes in the human genome. In contrast to microRNAs, piRNAs ...interact with PIWI proteins, another member of the Argonaute family, and function primarily in the nucleus. There, they are involved in the epigenetic silencing of transposable elements in addition to the transcriptional regulation of genes. It has recently been demonstrated that piRNAs are also expressed across a variety of human somatic tissue types in a tissue-specific manner. An increasing number of studies have shown that aberrant piRNA expression is a signature feature across multiple tumour types; however, their specific tumorigenic functions remain unclear. In this article, we discuss the emerging functional roles of piRNAs in a variety of cancers, and highlight their potential clinical utilities.
Coronaviruses are evolutionarily successful RNA viruses, common to multiple avian, amphibian and mammalian hosts. Despite their ubiquity and potential impact, knowledge of host immunity to ...coronaviruses remains incomplete, partly owing to the lack of overt pathogenicity of endemic human coronaviruses (HCoVs), which typically cause common colds. However, the need for deeper understanding became pressing with the zoonotic introduction of three novel coronaviruses in the past two decades, causing severe acute respiratory syndromes in humans, and the unfolding pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This renewed interest not only triggered the discovery of two of the four HCoVs, but also uncovered substantial cellular and humoral cross-reactivity with shared or related coronaviral antigens. Here, we review the evidence for cross-reactive B cell memory elicited by HCoVs and its potential impact on the puzzlingly variable outcome of SARS-CoV-2 infection. The available data indicate targeting of highly conserved regions primarily in the S2 subunits of the spike glycoproteins of HCoVs and SARS-CoV-2 by cross-reactive B cells and antibodies. Rare monoclonal antibodies reactive with conserved S2 epitopes and with potent virus neutralising activity have been cloned, underscoring the potential functional relevance of cross-reactivity. We discuss B cell and antibody cross-reactivity in the broader context of heterologous humoral immunity to coronaviruses, as well as the limits of protective immune memory against homologous re-infection. Given the bidirectional nature of cross-reactivity, the unprecedented current vaccination campaign against SARS-CoV-2 is expected to impact HCoVs, as well as future zoonotic coronaviruses attempting to cross the species barrier. However, emerging SARS-CoV-2 variants with resistance to neutralisation by vaccine-induced antibodies highlight a need for targeting more constrained, less mutable parts of the spike. The delineation of such cross-reactive areas, which humoral immunity can be trained to attack, may offer the key to permanently shifting the balance of our interaction with current and future coronaviruses in our favour.
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