From immunology to artificial intelligence: revolutionizing latent tuberculosis infection diagnosis with machine learning

Leveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision.

Therapeutic proteins can treat a myriad of diseases; however, their effectiveness is limited by short half-lives. Controlled release systems are advantageous because they prolong the action of protein drugs, minimize transient surges, and keep concentrations within a therapeutic range. Hydrogels are amenable to chemical modifications and comprise a versatile platform for controlled release, enabling minimally invasive injections at the injury site and acting as a depot to sustain the delivery of therapeutic proteins therefrom. Affinity-based release strategies have binding partners immobilized within the hydrogel to release proteins through noncovalent interactions and under mild conditions that maintain their three-dimensional architecture required for bioactivity. Naturally occurring binding interactions between therapeutic proteins and extracellular matrix components were advanced first but are inherently limited. Computational and experimental tools have emerged to enable high-specificity and moderate-affinity binding interactions to candidate therapeutic proteins. Directed evolution has enabled the development of novel peptide-, protein-, and aptamer-binding partners that modulate release from hydrogel delivery vehicles. With these tools, affinity-based systems that enable specific and tunable rates of release are being developed for diverse applications, including tissue regeneration and cancer treatment. These systems can now be tuned for the controlled release of multiple bioactive proteins. In this review, we examine the tools required to design novel binding partners for affinity-controlled release from hydrogels and provide insights into their formulations for specific applications. 

Engineering Hydrogels for Affinity-Based Release of Therapeutic Proteins

Background Monocyte miRNAs govern both protective and pathological responses during tuberculosis (TB) through their differential expression and emerged as potent targets for biomarker discovery and host-directed therapeutics. Thus, this study examined the miRNA profile of sorted monocytes across the TB disease spectrum [drug-resistant TB (DR-TB), drug-sensitive TB (DS-TB), and latent TB] and in healthy individuals (HC) to understand the underlying pathophysiology and their regulatory mechanism. Methods We sorted total monocytes including three subsets (HLA-DR+CD14+, HLA-DR+CD14+CD16+, and HLA-DR+CD16+cells) from peripheral blood mononuclear cells (PBMCs) of healthy and TB-infected individuals through flow cytometry and subjected them to NanoString-based miRNA profiling. Results The outcome was the differential expression of 107 miRNAs particularly the downregulation of miRNAs in the active TB groups (both drug-resistant and drug-sensitive). The miRNA profile revealed differential expression signatures: i) decline of miR-548m in DR-TB alone, ii) decline of miR-486-3p in active TB but significant elevation only in LTB iii) elevation of miR-132-3p only in active TB (DR-TB and DS-TB) and iv) elevation of miR-150-5p in DR-TB alone. The directionality of functions mediated by monocyte miRNAs from Gene Set Enrichment Analysis (GSEA) facilitated two phenomenal findings: i) a bidirectional response between active disease (activation profile in DR-TB and DS-TB compared to LTB and HC) and latent infection (suppression profile in LTB vs HC) and ii) hyper immune activation in the DR-TB group compared to DS-TB. Conclusion Thus, monocyte miRNA signatures provide pathological clues for altered monocyte function, drug resistance, and disease severity. Further studies on monocyte miRNAs may shed light on the immune regulatory mechanism for tuberculosis.

/pdf/downregulation-of-monocyte-mirnas-implications-for-immune-3d3dnqal.pdf

Downregulation of monocyte miRNAs: implications for immune dysfunction and disease severity in drug-resistant tuberculosis

Abstract Background Tuberculosis (TB) ranks as the second leading cause of death globally among all infectious diseases. This problem is likely due to the lack of biomarkers to differentiate the heterogeneous spectrum of infection. Therefore, the first step in solving this problem is to identify biomarkers to distinguish the different disease states of an individual and treat them accordingly. Circulating microRNA (miRNA) biomarkers are promising candidates for various diseases. In fact, we are yet to conceptualize how miRNA expression influences and predicts TB disease outcomes. Thus, this systematic review and meta-analysis aimed to assess the diagnostic efficacy of circulating miRNAs in Latent TB (LTB) and Active Pulmonary TB (PTB). Methods Literature published between 2012 and 2021 was retrieved from PubMed, Web of Science, Cochrane, Scopus, Embase, and Google Scholar. Articles were screened based on inclusion and exclusion criteria, and their quality was assessed using the QUADAS-2 tool. Funnel plots and forest plots were generated to assess the likelihood of study bias and heterogeneity, respectively. Results After the screening process, seven articles were selected for qualitative analysis. The study groups, which consisted of Healthy Control (HC) vs. TB and LTB vs. TB, exhibited an overall sensitivity of 81.9% (95% CI: 74.2, 87.7) and specificity of 68.3% (95% CI: 57.8, 77.2), respectively. However, our meta-analysis results highlighted two potentially valuable miRNA candidates, miR-197 and miR-144, for discriminating TB from HC. The miRNA signature model (miR197-3p, miR-let-7e-5p, and miR-223-3p) has also been shown to diagnose DR-TB with a sensitivity of 100%, but with a compromised specificity of only 75%. Conclusion miRNA biomarkers show a promising future for TB diagnostics. Further multicentre studies without biases are required to identify clinically valid biomarkers for different states of the TB disease spectrum. Systematic review registration PROSPERO (CRD42022302729). 

A systematic review and meta-analysis of circulating serum and plasma microRNAs in TB diagnosis

Background The early diagnosis of tuberculosis using novel non-sputum-based biomarkers is of high priority in the End TB strategy. MicroRNAs (miRNAs) are significant regulators of TB pathogenesis and their differential expression pattern among healthy, latent, and active TB population has revealed their potentiality as biomarkers in recent studies. Thus, we systematically reviewed and performed a meta-analysis on the role of host miRNAs in TB diagnosis. We also reviewed the involvement of miRNAs in the immune response to Mycobacterium tuberculosis (Mtb). Methods Pubmed, Ovid and Cochrane databases were searched to retrieve published literature from 2000 to 2020 using predefined keywords. We screened relevant studies based on inclusion and exclusion criteria and the included studies were assessed for their quality using STARD guidelines and QUADAS-2 tool. Funnel plots were constructed to assess the publication bias. The heterogeneity of studies and overall pooled results of sensitivity, specificity and DOR were determined using forest plots. Results We retrieved a total of 447 studies collectively from all the databases, out of which 21 studies were included for qualitative analysis. In these studies, miR-29, miR-31, miR-125b, miR146a and miR-155 were consistently reported. The overall sensitivity, specificity and DOR of these miRNAs were found to be 87.9% (81.7-92.2), 81.2% (74.5-86.5) and 43.1(20.3-91.3) respectively. Among these, miR-31 had the maximum diagnostic accuracy, with a sensitivity of 96% (89.7-98.5), specificity of 89% (81.2-93.8) and DOR of 345.9 (90.2-1326.3), meeting the minimal target product profile (TPP) for TB diagnostics. Conclusion miRNAs can thus be exploited as potential biomarkers for rapid detection of tuberculosis as evident from their diagnostic performance. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021226559 PROSPERO (CRD42021226559).

/pdf/micrornas-as-diagnostic-biomarkers-for-tuberculosis-a-133fv023.pdf

MicroRNAs as diagnostic biomarkers for Tuberculosis: A systematic review and meta- analysis

Peptide therapeutics have recently gained momentum in antiviral therapy due to their increased potency and cost-effectiveness. Interaction of the HIV-1 envelope gp120 with the host CD4 receptor is a critical step for viral entry, and therefore the CD4-binding site (CD4bs) of gp120 is a potential hotspot for blocking HIV-1 infection. The present study aimed to design short peptides from well-characterized CD4bs targeting broadly neutralizing antibodies (bNAbs), which could be utilized as bNAb mimetics for viral neutralization. Co-crystallized structures of HIV-1 gp120 in complex with CD4bs-directed bNAbs were used to derive hexameric peptides using the Rosetta Peptiderive protocol. Based on empirical insights into co-crystallized structures, peptides derived from the heavy chain alone were considered. The peptides were docked with both HIV-1 subtype B and C gp120, and the stability of the peptide–antigen complexes was validated using extensive Molecular Dynamics (MD) simulations. Two peptides identified in the study demonstrated stable intermolecular interactions with SER365, GLY366, and GLY367 of the PHE43 cavity in the CD4 binding pocket, and with ASP368 of HIV-1 gp120, thereby mimicking the natural interaction between ASP368gp120 and ARG59CD4–RECEPTOR. Furthermore, the peptides featured favorable physico-chemical properties for virus neutralization suggesting that these peptides may be highly promising bNAb mimetic candidates that may be taken up for experimental validation. Graphical Abstract Graphical flow chart of methodology.

/pdf/design-of-human-immunodeficiency-virus-1-neutralizing-9o6pp5q8.pdf

Design of human immunodeficiency virus-1 neutralizing peptides targeting CD4-binding site: An integrative computational biologics approach

SUMMARYA major impediment for HIV cure is the ability of the virus to integrate its genome in the form of replication-competent proviral DNA into the cellular genome of the host and remain transcriptionally silent and hidden from the host's immune defense mechanisms in latent reservoir cells. These latent reservoirs are highly heterogeneous, long-lived cells that are capable of reactivating to restore the viremic stage in virally suppressed individuals upon treatment interruption, thus necessitating life-long antiretroviral treatment. Latency reversal has become one of the most explored therapeutic approaches for eliminating HIV reservoirs and effecting HIV cure. Various aspects governing the establishment, maintenance, and reversal of HIV latency continue to be an enigma and warrant further research. Quantifying the size of the latent reservoir pool is also a challenge as these cells are very few in number and cannot be easily differentiated from uninfected cells. This article provides a comprehensive review of the in vitro and in vivo models currently available for studying HIV latency as well as the recently developed molecular tools for detection and quantification of latent viral reservoirs.

Experimental models for HIV latency and molecular tools for reservoir quantification-an update.

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MicroRNAs as diagnostic biomarkers for Tuberculosis: A systematic review and meta- analysis

Design of human immunodeficiency virus-1 neutralizing peptides targeting CD4-binding site: An integrative computational biologics approach

Experimental models for HIV latency and molecular tools for reservoir quantification-an update.