Biology subjects

Rothfuchs, A. G.

Publications and source records attributed to Rothfuchs, A. G..

4 recordsLinked to original sources

bioRxiv2021

SARS-CoV-2 Neurotropism and Single Cell Responses in Brain Organoids Containing Innately Developing Microglia

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection causes an extensive cell death and loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synaptic stripping. To a large extent, SARS-CoV-2 exposed microglia display a transcriptomic profile previously observed in neurodegenerative disorders characterized by early a synapse loss and an increased incident risk after a Covid-19 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from Covid-19.

neuroscience↗

bioRxiv2021

Intestinal helminth infection transforms the CD4+ T cell composition of the skin

Intestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, indicating effects on host immune responses in distal barrier tissues. We herein show that C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus have impaired capacity to initiate skin immune responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. Surprisingly, and in contrast to a previously noted loss of T cells in peripheral lymph nodes, the skin of worm-infected mice harboured higher numbers of CD4+ T cells compared to skin of uninfected controls. H. polygyrus-specific TH2 cells accumulated during infection and remained after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in blood and mesenteric lymph nodes draining intestinal tissues, indicating gut-to-skin trafficking of cells. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel mechanism for T cell colonization and worm-mediated immunosuppression in this organ.

immunology↗

bioRxiv2020

Vaccinia virus infection inhibits skin dendritic cell migration to draining lymph node

Despite the success of Vaccinia virus (VACV) against smallpox there remains a paucity of information on Dendritic cell (DC) responses to the virus, especially on the traffic of DCs and VACV to draining LN (dLN). Herein we studied skin DC migration in response to VACV and compared it to the tuberculosis vaccine Mycobacterium bovis Bacille Calmette-Guerin (BCG), another live-attenuated vaccine administered via the skin. In stark contrast to BCG, skin DCs did not relocate to dLN in response to VACV. This happened in spite of virus-induced accumulation of several other innate-immune cell populations in the dLN. UV inactivation of VACV or use of the Modified Vaccinia virus Ankara (MVA) strain promoted DC movement to dLN, indicating that the virus actively interferes with skin DC migration. This active immune suppression by VACV was potent enough to ablate the mobilization of skin DCs in response to BCG, and to reduce the transport of BCG to dLN. Expression of inflammatory mediators associated with BCG-triggered DC migration were absent from virus-injected skin, suggesting that other pathways provoke DC movement in response to replication-deficient VACV. Despite viral suppression of DC migration, VACV was detected in dLN much earlier than BCG, indicating a rapid, alternative route of viral traffic to dLN despite marked blockade of skin DC mobilization from the site of infection.

immunology↗

bioRxiv2020

Operative and technical modifications to the Coriolis(R) μ air sampler that improve sample recovery and biosafety during microbiological air sampling

Detecting infectious aerosols is central for gauging and countering airborne threats. In this regard the Coriolis(R) {micro} cyclonic air sampler is a practical, commercial collector that can be used with various analysis methods to monitor pathogens in air. However, information on how to operate this unit under optimal sampling and biosafety conditions is limited. We investigated Coriolis performance in aerosol dispersal experiments with polystyrene microspheres and Bacillus globigii spores. We report inconsistent sample recovery from the collector cone due to loss of material when sampling continuously for more than 30 min. Introducing a new collector cone every 10 min improved this shortcoming. Moreover, we found that several surfaces on the device become contaminated during sampling. Adapting a HEPA-filter system to the Coriolis prevented contamination without altering collection efficiency or tactical deployment. A Coriolis modified with these operative and technical improvements was used to collect aerosols carrying microspheres released inside a Biosafety Level-3 laboratory during simulations of microbiological spills and aerosol dispersals. In summary, we provide operative and technical solutions to the Coriolis that optimize microbiological air sampling and improve biosafety.

microbiology↗