Host-directed immunotherapy of viral and bacterial infections: past, present and future

Wallis, Robert S.; O’Garra, Anne; Sher, Alan; Wack, Andreas

doi:10.1038/s41577-022-00734-z

Cited by 132 publications

(84 citation statements)

References 170 publications

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“…Therapies involving immune blockade/modulation are revolutionizing the treatment of many cancers 1−3 and are also being investigated for the treatment of both viral 4 and bacterial 5 infections, e.g., through host-directed therapies or modulation of the host immune response to infection. 4 Within this context, chemical tools have been increasingly investigated to dissect and manipulate immune responses. 6,7 The mannose receptor (MR, CD206) is an endocytic receptor that selectively binds an extensive range of both endogenous and exogenous ligands and is widely expressed by key immune cells such as tissue macrophages, selected populations of dendritic cells (DCs), and nonvascular endothelium.…”

Section: ■ Introductionmentioning

confidence: 99%

Sulfation at Glycopolymer Side Chains Switches Activity at the Macrophage Mannose Receptor (CD206) In Vitro and In Vivo

et al. 2022

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The mannose receptor (CD206) is an endocytic receptor expressed by selected innate immune cells and nonvascular endothelium, which plays a critical role in both homeostasis and pathogen recognition. Although its involvement in the development of several diseases and viral infections is well established, molecular tools able to both provide insight on the chemistry of CD206-ligand interactions and, importantly, effectively modulate its activity are currently lacking. Using novel SO4-3-Gal-glycopolymers targeting its cysteine-rich lectin ectodomain, this study uncovers and elucidates a previously unknown mechanism of CD206 blockade involving the formation of stable intracellular SO4-3-Gal-glycopolymer–CD206 complexes that prevents receptor recycling to the cell membrane. Further, we show that SO4-3-Gal glycopolymers inhibit CD206 both in vitro and in vivo, revealing hitherto unknown receptor function and demonstrating their potential as CD206 modulators within future immunotherapies.

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Section: ■ Introductionmentioning

confidence: 99%

Sulfation at Glycopolymer Side Chains Switches Activity at the Macrophage Mannose Receptor (CD206) In Vitro and In Vivo

et al. 2022

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“…Therefore, adjunct host-directed therapy with a GPR183 antagonist together with conventional antivirals may increase treatment efficacy. Since a GPR183 antagonist targets the host and not the virus it is not anticipated that viruses will develop resistance against host directed therapy (49). Further, a GPR183 antagonist-based therapy can also be immediately effective against newly emerging SARS-CoV-2 variants without further adaption.…”

Section: Discussionmentioning

confidence: 99%

Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection

Foo¹,

Bartlett²,

Chew³

et al. 2022

Preprint

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Rationale: Severe viral respiratory infections are often characterized by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain elusive. Objectives: To identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. Methods: Preclinical murine models of influenza virus and SARS-CoV-2 infection. Results: Oxidized cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte-macrophage infiltration to the lung during influenza virus (IAV) and SARS-CoV-2 infections. Both IAV and SARS-CoV-2 infections upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidized cholesterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol (7α,25-OHC). Loss-of-function mutation of GPR183, or treatment with a GPR183 antagonist, reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist also significantly attenuated the severity of SARS-CoV-2 infection by reducing weight loss and viral loads. Conclusion: This study demonstrates that oxysterols drive inflammation in the lung and provides the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe viral respiratory infections.

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“…Because HDTs do not directly select against the bacteria, they are less likely to engender resistance compared to antibiotics. Some HDTs interfere with the capacity of Mtb to subvert host systems, whereas others regulate immune responses, so as to induce novel responses or target deficiencies in individuals with active disease (81). Drug discovery efforts have traditionally focused on drugs targeting specific processes with minimal off-target effects, though recent efforts, for example with COVID-19, have targeted hyperinflammatory pathways as a means to limit tissue damage (81).…”

Section: Discussionmentioning

confidence: 99%

“…Some HDTs interfere with the capacity of Mtb to subvert host systems, whereas others regulate immune responses, so as to induce novel responses or target deficiencies in individuals with active disease (81). Drug discovery efforts have traditionally focused on drugs targeting specific processes with minimal off-target effects, though recent efforts, for example with COVID-19, have targeted hyperinflammatory pathways as a means to limit tissue damage (81). Such approaches can be complex to implement, requiring proper timing and dosing to limit tissue damage while still permitting requisite inflammatory responses that contain the infection.…”

Section: Discussionmentioning

confidence: 99%

The host-directed therapeutic imatinib mesylate accelerates immune responses toMycobacterium marinuminfection and limits pathology associated with granulomas

Cleverley

Peddineni

Guarner

et al. 2022

Preprint

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Mycobacterial infections, including those caused by members of the mycobacterium tuberculosis complex [MTC] and Nontuberculous mycobacteria [NTM], can induce widespread morbidity and mortality in people. Mycobacterial infections cause both a delayed immune response, which limits rate of bacterial clearance, and formation of granulomas, which contain bacterial spread, but also contribute to lung damage, fibrosis, and morbidity. Granulomas also limit access of antibiotics to bacteria, which may facilitate development of resistance. MTC members resistant to some or all antibiotics are estimated to account for a third of deaths from tuberculosis [TB], and newly developed antibiotics have already engendered resistance, pointing to the need for new therapeutic approaches. Imatinib mesylate, a cancer drug used to treat chronic myelogenous leukemia [CML] that targets Abl and related tyrosine kinases, is a possible host-directed therapeutic [HDT] for mycobacterial infections, including TB. Here, we use the murine Mycobacterium marinum [Mm] infection model, which forms quantifiable granulomas on the tails, in conjunction with transcriptomic analysis of the tail lesions. The data indicate that imatinib induces gene signatures indicative of immune activation at early time points post infection that resemble those seen at later ones, suggesting that imatinib accelerates but does not substantially alter anti-mycobacterial immune responses. Moreover, focusing on the TNFα pathway, which is induced by imatinib, we show that imatinib promotes cell survival in infected bone marrow-derived macrophages [BMDMs] in a manner that depends on caspase 8. Moreover, imatinib limits formation and growth of granulomas, an effect abrogated in mice lacking caspase 8. These data provide evidence for the utility of imatinib as an HDT for mycobacterial infections in accelerating immune responses, and limiting pathology associated with granulomas, and thus mitigating post-treatment morbidity.

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Host-directed immunotherapy of viral and bacterial infections: past, present and future

Cited by 132 publications

References 170 publications

Sulfation at Glycopolymer Side Chains Switches Activity at the Macrophage Mannose Receptor (CD206) In Vitro and In Vivo

Sulfation at Glycopolymer Side Chains Switches Activity at the Macrophage Mannose Receptor (CD206) In Vitro and In Vivo

Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection

The host-directed therapeutic imatinib mesylate accelerates immune responses toMycobacterium marinuminfection and limits pathology associated with granulomas

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