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Dr. Vivek Thacker - Microphysiological systems: bottom-up tools for studying host-pathogen interactions

Vivek Thacker

EPFL, Lausanne, Switzerland

Microphysiological systems: bottom-up tools for studying host-pathogen interactions

Alveoli are a vast majority of the surface area of the lung. These structures are lined by epithelial cells exposed to air and separated by a thin basement membrane from the lung microvasculature to enable rapid gas exchange. They are only sparsely populated by resident immune cells, but nevertheless must mount an effective challenge against aerosolised pathogens contained within the ca. 8000-9000 litres of air that an adult human breathes in daily. Alveoli are therefore ideally suited to modelling by microphysiological systems such as organ-on-chip devices [1] that recreate aspects of host physiology in a bottom-up, modular, and tuneable fashion. As model systems, they occupy the vast middle ground between typical cellular monoculture models and animal models and offer new tools to probe the dynamics of immune response, either through live-cell imaging or in situ gene expression. In my talk, I will discuss work over the past few years on studies of host-pathogen interactions in early tuberculosis and, more recently, COVID-19.

Tuberculosis - caused by the bacterium Mycobacterium tuberculosis remains a significant cause of global mortality with a vast spectrum of disease outcomes. Using a murine lung-on-chip model, we studied ‘first contact’ with the host and uncovered a key role for epithelial-cell-produced pulmonary surfactant in attenuating early bacterial growth and generating a fraction of non-growing cells [2]. In contrast, in deficient surfactant conditions, bacterial growth was significantly faster than in liquid cultures, which together revealed a key role for the air-liquid interactions and surfactant levels in early host-pathogen interactions. A second line of enquiry focused on changes to bacterial physiology; we observed that cord-like bacterial growth occurred prominently at the air-liquid interface. Particularly within epithelial cells, these structures can grow in-between cells and remain hidden away from the immune cells. These observations have been correlated with histological observations in the mouse model and suggest that mycobacterial cording may be a means to enable bacterial spread into deeper areas of the lung interstitium where this disease eventually takes root.

Lastly, I will describe our efforts in understanding the pathogenesis of the betacoronavirus SARS-CoV-2 in the alveolar space [3]; a site of severe infection that has been relatively understudied. Consistent with monoculture reports, we observe low numbers of SARS-CoV-2 virions released apically from alveolar epithelial cells. However, basolateral transmission leads to rapid infection of the underlying endothelial layer and the transient generation of hyperplasic cells. We observe a progressive loss of endothelial barrier integrity, which do not occur if these cells are exposed to the virus apically. In situ RNA hybridisation shows that viral RNA persists in individual cells, which generates a response that is skewed towards NF-KB mediated inflammation, is typified by IL-6 secretion even in the absence of immune cells, and is transient in epithelial cells but persistent in endothelial cells. Finally, we find that perfusion with the IL-6R antibody Tocilizumab slows the loss of barrier integrity but does not reduce the occurrence of the hyperplasia. The lung-on-chip model is therefore able to recapitulate the endothelialitis reported in multiple autopsies [4]. Inflammation occurs despite a lack of rapid viral replication, in a cell-type specific manner and independently of immune-cell mediated cytokine storms, whose effect would only exacerbate the damage.


[1] D. Huh et al. Reconstituting organ-level lung functions on a chip. Science 328 (5986) 1662-1668 (2010)

[2] V. V. Thacker et al. A lung-on-chip model reveals an essential role for alveolar epithelial cells in controlling bacterial growth during early tuberculosis. bioRxiv doi: 10.1101/2020.02.03.931170 (2020, accepted at eLife)

[3] V. V. Thacker et al. Rapid endothelialitis and vascular inflammation characterise SARS-CoV-2 infection in a human lung-on-chip model. bioRxiv doi: 10.1101/2020.08.10.243220 (2020, under review)

[4] M. Ackermann et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 383 120-128 (2020)


Registration to attend the webinar: click HERE

Contact: Olivier Neyrolles (


24 Nov

11:00 - 12:00

Online seminar