Biology subjects

Rocha, H. L.

Publications and source records attributed to Rocha, H. L..

4 recordsLinked to original sources

bioRxiv2026

IFNγ-Driven Inflammatory Responses in the Nasal Mucosa Drive Influenza Virus Shedding and Transmission

What determines host infectiousness during influenza A virus (IAV) infection remains a fundamental unanswered question in virology. While upper respiratory tract (URT) replication is necessary for transmission, its insufficient to explain host-to-host variation in contagiousness. Using the infant mouse model of influenza transmission, we show that viruses containing H3 hemagglutinin shed at higher levels than non-H3-containing viruses, despite comparable URT replication. H3-containing virus infection was associated with higher URT inflammation, characterized by increased cytokine production, immune cell recruitment, and mucus hypersecretion, which directly correlated with shedding efficiency. Transcriptomic profiling identified enrichment of interferon-stimulated gene programs, with a dominant interferon gamma (IFN{gamma}) signature during H3 infections. Functional studies demonstrated that IFN{gamma} deficiency reduced mucus production, shedding, and transmission, whereas IFN{gamma} supplementation restored these phenotypes. Together, these findings identify IFN{gamma}-driven mucosal inflammation key host determinant of influenza infectiousness, reframing contagiousness as a consequence of host inflammatory clearance rather than viral replication alone.

microbiology↗

bioRxiv2023

Digitize your Biology! Modeling multicellular systems through interpretable cell behavior

Cells are fundamental units of life, constantly interacting and evolving as dynamical systems. While recent spatial multi-omics can quantitate individual cells characteristics and regulatory programs, forecasting their evolution ultimately requires mathematical modeling. We develop a conceptual framework--a cell behavior hypothesis grammar--that uses natural language statements (cell rules) to create mathematical models. This allows us to systematically integrate biological knowledge and multi-omics data to make them computable. We can then perform virtual "thought experiments" that challenge and extend our understanding of multicellular systems, and ultimately generate new testable hypotheses. In this paper, we motivate and describe the grammar, provide a reference implementation, and demonstrate its potential through a series of examples in tumor biology and immunotherapy. Altogether, this approach provides a bridge between biological, clinical, and systems biology researchers for mathematical modeling of biological systems at scale, allowing the community to extrapolate from single-cell characterization to emergent multicellular behavior.

systems biology↗

bioRxiv2023

Targeting host sialic acids in the upper respiratory tract with a broadly-acting neuraminidase to inhibit influenza virus transmission

The ongoing transmission of influenza A viruses (IAV) for the past century continues to be a burden to humans. IAV binds terminal sialic acids (SA) of sugar molecules present within the upper respiratory tract (URT) in order to successfully infect hosts. The two most common SA structures that are important for IAV infection are those with 2,3- and 2,6-linkages. While mice were once considered to be an unsuitable system for studying IAV transmission due to their lack of 2,6-SA in the trachea, we have successfully demonstrated that IAV transmission in infant mice is remarkably efficient. This finding led us to reevaluate the SA composition of the URT of mice using in situ immunofluorescence and examine its in vivo contribution to transmission for the first time. We demonstrate that mice express both 2,3- and 2,6-SA in the URT and that the difference in expression between infants and adults contribute to the variable transmission efficiencies observed. Furthermore, selectively blocking 2,3-SA or 2,6-SA within the URT of infant mice using lectins was necessary but insufficient at inhibiting transmission, and simultaneous blockade of both receptors was crucial in achieving the desired inhibitory effect. By employing a broadly-acting neuraminidase (ba-NA) to indiscriminately remove both SA moieties in vivo, we effectively suppressed viral shedding and halted the transmission of different strains of influenza viruses. These results emphasize the utility of the infant mouse model for studying IAV transmission, and strongly indicate that broadly targeting host SA is an effective approach that inhibits IAV contagion. IMPORTANCEInfluenza virus transmission studies have historically focused on viral mutations that alter hemagglutinin binding to sialic acid (SA) receptors in vitro. However, SA binding preference doesnt fully account for the complexities of IAV transmission in humans. Our previous findings reveal that viruses that are known to bind 2,6-SA in vitro have different transmission kinetics in vivo, suggesting that diverse SA interactions may occur during their life-cycle. In this study, we examine the role of host SA on viral replication, shedding, and transmission in vivo. We highlight the critical role of SA presence during virus shedding, such that attachment to SA during virion egress is equally important as detachment from SA during virion release. These insights support the potential of broadly-acting neuraminidases as therapeutic agents capable of restraining viral transmission in vivo. Our study unveils intricate virus-host interactions during shedding, highlighting the necessity to develop innovative strategies to effectively target transmission.

microbiology↗

bioRxiv2021

A persistent invasive phenotype in post-hypoxic tumor cells is revealed by novel fate-mapping and computational modeling

Hypoxia is a critical factor in solid tumors that has been associated with cancer progression and aggressiveness. We recently developed a hypoxia-fate mapping system that allowed the tracing of post-hypoxic cells within a tumor for the first time. This novel approach, based on an oxygen-dependent fluorescent switch, made the investigation of the post-hypoxic phenotype possible. The system allowed us to measure key biological features such as oxygen distribution, cell proliferation and migration. Using this data, we developed a computational model to investigate the motility and phenotypic persistence of hypoxic and post-hypoxic cells during tumor progression. The behavior of hypoxic and post-hypoxic cells was defined by phenotypic persistence time, cell movement bias and the fraction of cells that respond to an enhanced migratory stimulus. Our studies revealed that post-hypoxic cells have an enhanced persistent migratory phenotype that promotes the formation of invasive structures ("plumes") expanding towards the oxygenated tumor regions. This work combined advanced cell tracking and imaging techniques with mathematical modeling, and revealed for the first time that a persistent invasive migratory phenotype that develops under hypoxic conditions enhances their escape into non-hypoxic tumor regions to invade the surrounding tissue.

cancer biology↗