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Host-directed therapies (HDTs) are emerging as a potential valid support in the treatment of drug-resistant tuberculosis (TB). Following our recent report indicating that genetic and pharmacological inhibition of transglutaminase 2 (TG2) restricts ( ) replication in macrophages, we aimed to investigate the potentials of the TG2 inhibitors cystamine and cysteamine as HDTs against TB. We showed that both cysteamine and cystamine restricted replication in infected macrophages when provided at equimolar concentrations and did not exert any antibacterial activity when administered directly on cultures. Interestingly, infection of differentiated THP-1 mRFP-GFP-LC3B cells followed by the determination of the autophagic intermediates pH distribution (AIPD) showed that cystamine inhibited the autophagic flux while restricting replication. Moreover, both cystamine and cysteamine had a similar antimicrobial activity in primary macrophages infected with a panel of clinical strains belonging to different phylogeographic lineages. Evaluation of cysteamine and cystamine activity in the human model of granuloma-like structures (GLS) further confirmed the ability of these drugs to restrict replication and to reduce the size of GLS. The antimicrobial activity of the TG2 inhibitors synergized with a second-line anti-TB drug as amikacin in human monocyte-derived macrophages and in the GLS model. Overall, the results of this study support the potential usefulness of the TG2-inhibitors cysteamine and cystamine as HDTs against TB.

Tuberculosis (TB) remains a significant public health concern in the 21st century, especially due to drug resistance, coinfection with diseases like immunodeficiency syndrome (AIDS) and coronavirus disease 2019, and the lengthy and costly treatment protocols. In this review, we summarize the pathogenesis of TB infection, therapeutic targets, and corresponding modulators, including first‐line medications, current clinical trial drugs and molecules in preclinical assessment. Understanding the mechanisms of Mycobacterium tuberculosis ( Mtb ) infection and important biological targets can lead to innovative treatments. While most antitubercular agents target pathogen‐related processes, host‐directed therapy (HDT) modalities addressing immune defense, survival mechanisms, and immunopathology also hold promise. Mtb ’s adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti‐TB drug development efforts.

Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to cause pulmonary cavitation and dissemination in the tissues. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading all components of pulmonary extracellular matrix (ECM). It is well established that Mtb infection leads to upregulation of MMPs and also causes disturbance in the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thus altering the extracellular matrix deposition. In TB, secretion of MMPs is mainly regulated by NF‐κB, p38 and MAPK signalling pathways. In addition, recent studies have demonstrated the immunomodulatory roles of MMPs in Mtb pathogenesis. Researchers have proposed a new regimen of improved TB treatment by inhibition of MMP activity to hinder matrix destruction and to minimize the TB‐associated morbidity and mortality. The proposed regimen involves adjunctive use of MMP inhibitors such as doxycycline, marimastat and other related drugs along with front‐line anti‐TB drugs to reduce granuloma formation and bacterial load. These findings implicate the possible addition of economical and well‐tolerated MMP inhibitors to current multidrug regimens as an attractive mean to increase the drug potency. Here, we will summarize the recent advancements regarding expression of MMPs in TB, their immunomodulatory role, as well as their potential as therapeutic targets to control the deadly disease.

Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony‐stimulating factor (M‐CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M‐CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon‐γ. This depended upon M‐CSF‐induced myelopoiesis leading to IL15Rα‐mediated presentation of IL‐15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M‐CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G‐CSF‐mobilized hematopoietic stem and progenitor cells. Together, M‐CSF‐induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M‐CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host‐directed therapies. Synopsis Herpesviridae like CMV are a major cause of morbidity and mortality in patients after HCT. Therapies reconstituting the host's antiviral immunocompetence for prophylaxis and treatment are an unmet medical need since licensed therapies are either insufficiently effective or have severe side effects. M‐CSF protects from lethal murine CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression, by rapidly reconstituting donor hematopoietic stem and progenitor cells. M‐CSF stimulates a coordinated myeloid and NK cell differentiation program resulting in increased NK cell numbers and activity, which depends on M‐CSF‐induced myelopoiesis generating IL‐15‐producing monocytes and I‐IFN‐producing pDCs. No impairment of long‐term hematopoietic stem cell engraftment or acute graft‐versus‐host‐disease after M‐CSF treatment was observed. In G‐CSF‐mobilized human PBMCs M‐CSF also stimulates monopoiesis, IL15Rα expression in monocytes and functional NK cell differentiation. M‐CSF could provide a general host‐directed antiviral cytokine therapy, to complement pathogen‐directed antiviral therapies in immunosuppressed conditions beyond HCT, such as post‐chemotherapy leukopenia or septicemia. Graphical Abstract Herpesviridae like CMV are a major cause of morbidity and mortality in patients after HCT. Therapies reconstituting the host's antiviral immunocompetence for prophylaxis and treatment are an unmet medical need since licensed therapies are either insufficiently effective or have severe side effects.

Sepsis is a dynamic syndrome of infection-driven metabolic and immune dysregulation in which oxidative stress can escalate into an \"oxidative storm,\" promoting organ dysfunction and maladaptive host responses. Within this context, ferroptosis represents a metabolically constrained form of regulated necrotic cell death driven by iron-dependent lipid peroxidation, linking redox collapse to tissue injury in sepsis. Emerging evidence suggests that autophagy critically shapes ferroptosis susceptibility by regulating intracellular iron mobilization, membrane lipid substrate availability, mitochondrial quality control, and energy-stress signaling. This review therefore frames autophagy-ferroptosis crosstalk in sepsis as a host metabolic vulnerability and discusses how mechanism-guided, host-directed antioxidant nanomedicine may help preserve tissue integrity while limiting interference with antimicrobial defense. We explored how autophagy modulates ferroptosis susceptibility by regulating iron metabolism, lipid substrate availability, and mitochondrial quality control. Building on this framework, we evaluated emerging antioxidant nanomedicines targeting key intervention points, including iron chelation, catalytic ROS/RNS scavenging, membrane-localised radical trapping, mitochondria-targeted source control, and enhancement of endogenous defences. Organ- and immune-specific effects are highlighted, emphasizing the need for aligned biochemical readouts, flux-aware autophagy evaluation, and stage-specific therapeutic targeting. Finally, we outline translational priorities for precision redox modulation in sepsis, focusing on biomarker-guided patient stratification, compartment-specific delivery, and biosafety considerations.

Tuberculosis (TB) treatment is severely hampered by the rise in multi-drug-resistant strains and the prevalence of drug-induced toxicities. Host-Directed Therapies (HDTs) have emerged as a promising strategy to overcome these challenges by modulating innate immunity and circumventing (Mtb) evasion mechanisms. A hallmark of Mtb pathogenesis is the arrest of phagosome maturation and the induction of host cell necrosis over protective apoptosis. In this study, we investigated the potential HDT effects of α-Lipoic acid (α-LA), a well-known antioxidant and metabolic cofactor, within an in vitro model of Mtb-infected THP-1 macrophages. Our findings indicate that α-LA treatment modulates the macrophage redox state and selectively promotes apoptosis in infected cells without increasing necrotic lysis. Furthermore, α-LA administration led to a significant, dose-dependent restoration of phagolysosome acidification, effectively reversing the maturation blockade imposed by Mtb. Notably, this enhanced acidification inversely correlated with intracellular bacterial survival. These results suggest that α-LA might act as a multifaceted HDT agent capable of restoring both host-protective cell death and phagosomal microbicidal mechanisms. Given its established safety profile and its ability to complement standard anti-TB drugs like Bedaquiline (BDQ), α-LA represents a highly promising candidate for adjunct therapy to improve TB treatment outcomes and mitigate the impact of antibiotic resistance.

Influenza virus infections and their associated morbidity and mortality are a major threat to global health. Vaccination is an effective influenza prevention measure; however, the effectiveness is challenged by the rapid changes in the influenza virus genome leading to viral adaptation. Emerging viral resistance to the neuraminidase inhibitor oseltamivir limits the treatment of acute influenza infections. Targeting influenza virus-host interactions is a new and emerging field, and therapies based on the combination of virus- and host-directed drugs might significantly improve treatment success. We therefore assessed the combined treatment with oseltamivir and the repurposed antifungal drug itraconazole on infection of polarized broncho-epithelial Calu-3 cells with pdm09 or Panama influenza A virus strains. We detected significantly stronger antiviral activities in the combined treatment compared to monotherapy with oseltamivir, permitting lower concentrations of the drug than required for the single treatments. Bliss independence drug interaction analysis indicated that both drugs acted independently of each other. The additional antiviral effect of itraconazole might safeguard patients infected with influenza virus strains with heightened oseltamivir resistance.

Pulmonary infections and fibrosis remain difficult to treat because current interventions target isolated pathways rather than the coupled axes of inflammation, barrier integrity, and tissue remodeling. Here, it is shown that inhalationally delivered, lung‐targeted antisense oligonucleotides against angiopoietin‐like 4 (Angptl4‐ASO) attenuate both infectious and fibrotic lung disease. In murine models of bacterial and viral pneumonia, Angptl4‐ASO reduces inflammatory cell infiltration, preserves alveolar architecture, and improves host defence. In bleomycin‐induced fibrosis, treatment lowered Ashcroft scores, collagen deposition, and α‐smooth muscle actin (SMA) expression, indicating broad efficacy across acute and chronic injury. Comparative transcriptomics reveal model‐specific responses, immune and oxidative‐stress programs in pneumonia versus extracellular matrix (ECM)‐remodeling pathways in fibrosis, yet nearly half of all changes converge on a shared ANGPTL4‐regulated network linking hypoxic, inflammatory, apoptotic, and stress response programs. This conserved signature suggests that ANGPTL4 functions as a central regulator of injury resolution regardless of the initiating insult. Mechanistically, Angptl4‐ASO reinforced epithelial barrier integrity through coordinated regulation of tight junction and glycoprotein pathways. Longitudinal tracking of a Sulfo‐Cyanine 5 (Cy5)‐conjugated Angptl4‐ASO confirmed a lung‐retentive biodistribution, with sustained intrapulmonary localization and minimal systemic dissemination over a 144‐hour window. Collectively, these findings position inhaled ANGPTL4‐ASO as a host‐directed, multi‐axis therapeutic strategy that addresses shared and context‐specific drivers of diverse pulmonary pathologies. Inhaled antisense oligonucleotides targeting ANGPTL4 attenuate inflammation, preserve barrier integrity, and reduce fibrosis in both infectious and sterile lung injury models. Integrated transcriptomic analysis reveals a conserved ANGPTL4‐regulated gene network coordinating hypoxic, inflammatory, apoptotic, and stress‐response pathways. This work establishes a lung‐retentive, host‐directed therapeutic strategy that targets shared and context‐specific drivers of pulmonary disease — spanning viral, bacterial, and idiopathic respiratory conditions as well as fibrosis.

Influenza A virus (IAV) infection is a significant risk factor for invasive pulmonary aspergillosis, particularly in severe influenza patients, where the incidence and mortality of influenza‐associated pulmonary aspergillosis (IAPA) are markedly elevated. IAPA creates a state of acute acquired immunodeficiency in patients who were previously healthy, challenging the traditional view of fungal disease as a condition restricted to the classically immunocompromised. Drawing on emerging evidence, this review maps out the pathogenesis of IAPA as a specific, sequential cascade of host failure. The process begins with barrier disruption, where the virus induces Type III interferons and interleukin‐1β (IL‐1β) signalling to arrest epithelial repair and compromise tissue integrity. This is followed by recognition failure, characterized by the specific depletion of innate B1a lymphocytes and natural IgG antibodies, rendering fungal spores undetectable to phagocytes. The final stage is effector paralysis, where a cytokine storm drives neutrophil oxidative shutdown and transcriptional suppression. Ultimately, IAPA is a disorder of functional dissociation: The body is hyper‐inflamed, yet its antimicrobial metabolism is paralysed. Understanding this framework reveals precise therapeutic windows for host‐directed interventions, such as timed IL‐1 receptor blockade or nebulized immunostimulants, which can restore immune competence and improve clinical outcomes. From barrier dysfunction to metabolic paralysis: IAPA progression is characterized by a functional dissociation: the host experiences hyper‐inflammatory cytokine storms (IL‐1β, IFN‐λ) while simultaneously suffering from antimicrobial metabolic paralysis (loss of ROS and recognition). This creates a specific window for host‐directed therapies, including IL‐1 receptor blockade to restore neutrophil function and immunostimulants to re‐engage host defences.

Salmonella enterica, a major cause of gastroenteritis and typhoid fever, hijacks host machinery to invade cells, and replicate within a specialized niche. While some host factors are known, a comprehensive, temporally‐resolved understanding of the host‐pathogen interface has been hindered by a lack of suitable genome‐wide methodologies. To address this, a parallel CRISPR screening platform is developed to identify host determinants for distinct infection stages. An invasion screen captured factors for bacterial entry, while a fitness screen identified factors governing long‐term survival. The screens reveal a temporal switch in host dependency, from endosomal trafficking in early infection to cell cycle and DNA damage response pathways governing host cell fitness in long‐term infection. Notably, the approach uncovers two novel host factors with stage‐specific roles, SORL1 as a mediator of bacterial invasion and ZFYVE19 as a factor supporting intracellular proliferation. Genetic disruption of SORL1 or ZFYVE19 validate these roles, leading to impaired invasion or replication, respectively. Importantly, antibody‐mediated blockade of SORL1 effectively prevented Salmonella entry, highlighting it as a novel host‐directed therapeutic target. Together, the screening strategy provides a powerful framework for the temporal dissection of host‐pathogen interactions, revealing novel biology and promising therapeutic targets. To distinguish how Salmonella invades cells vs how it survives long‐term, a parallel CRISPR screening platform is developed. This approach reveals the host proteins that the bacterium exploits at different stages of infection. The study identifies SORL1 as a novel host factor for invasion and demonstrates that blocking it with an antibody effectively prevents infection, revealing a novel host‐directed therapeutic strategy.