Monocytes and dendritic cells : roles during human influenza and hantavirus infections

Viruses infect a vast majority of the other species on the planet and rarely leave the host undamaged. Most human viruses need to infect an individual to replicate and disseminate, and must contend with the full force of the human immune system. On the host side, immune cells must withstand virus infection, impairment of function and possible death, to recruit other immune cells, train them against the specific weaknesses of the adversary, muster a host, eliminate the threat, and leave behind a legacy of sentinels who maintain immune memory. Host-pathogen interactions are, in many ways, like warfare. In this thesis, we describe an important early aspect of the human immune response to two re-emerging viruses of global importance– influenza viruses and hantaviruses. Both influenza viruses and hantaviruses are pathogens which enter through the respiratory route but cause vastly different diseases. A strong, proinflammatory innate response is mounted against influenza viruses, but clearance of virus is carried out by antigen-specific adaptive responses. On the other hand, hantavirus disease is only recognizable once the host immune response has injured the vasculature and starting the cascade of hemorrhagic events associated with the disease. In both instances, the adaptive responses rely on efficient programming and specification by innate immune cells including monocytes and dendritic cells (DCs). In this thesis, we investigated the different roles played by monocytes and DCs during human influenza A virus (IAV) and Puumala orthohantavirus infections.

We first investigated the functional differences between human plasmacytoid DCs (PDCs) from different tissues in the context of IAV infection. We found that PDCs in blood are more potent producers of the antiviral mediator, IFNα, than tonsil-resident PDCs. Next, we studied the distribution and function of monocytes and DCs in circulation and in the upper respiratory tract during acute influenza disease. We observed that IAV infection resulted in expansion of specialized inflammatory monocytes in circulation which cause inflammation via TNFα. Additionally, monocytes and DCs were recruited to the nasopharynx, where the virus is typically located and we found significant evidence of local TNFα and inflammation. To assess whether monocyte and DC redistribution is also provoked by hantavirus infections, we studied patients suffering from hemorrhagic fever with renal syndrome (HFRS) due to Puumala orthohantavirus. We report a dramatic loss of monocytes and DCs in peripheral circulation during acute HFRS and indications of migratory chemokine signaling. And finally, we assessed the influence of disease severity on monocyte redistribution in acute HFRS. We found that severe HFRS is characterized by depletion of nonclassical monocytes from circulation and impairment of myeloid cell ability to respond to additional TLR stimuli. The findings in this thesis indicate tissue- and pathogen-specific differences in inflammatory behavior of human monocytes and DCs.

List of scientific papers

I. Sindhu Vangeti, Jens Gertow, Meng Yu, Sang Liu, Faezzah Baharom, Saskia Scholz, Danielle Friberg, Magnus Starkhammar, Alexander Ahlberg, and Anna Smed-Sörensen. Human blood and tonsil plasmacytoid dendritic cells display similar gene expression profiles but exhibit differential type I IFN responses to influenza A virus infection. Journal of Immunology. 2019, 202(7):2069-2081.
https://doi.org/10.4049/jimmunol.1801191

II. Sindhu Vangeti, Meng Yu, Sara Falck-Jones, Sang Liu, Asghar Muhammad, Klara Sondén, Jan Albert, Niclas Johansson, Anna Färnert, Anna Smed-Sörensen. Human influenza A virus infection recruits monocytes and dendritic cells to the nasopharynx in patients with acute disease. [Manuscript]

III. Saskia Scholz, Faezzah Baharom, Gregory Rankin, Kimia T. Maleki, Shawon Gupta, Sindhu Vangeti, Jamshid Pourazar, Andrea Discacciati, Jonas Höijer, Matteo Bottai, Niklas Björkström, Johan Rasmuson, Magnus Evander, Anders Blomberg, Hans-Gustaf Ljunggren, Jonas Klingström, Clas Ahlm and Anna Smed-Sörensen. Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways. PLoS Pathogens. 2017, 13(6):e1006462.
https://doi.org/10.1371/journal.ppat.1006462

IV. Sindhu Vangeti*, Tomas Strandin*, Sang Liu, Johanna Tauriainen, Jukka Mustonen, Antti Vaheri, Olli Vapalahti, Jonas Klingström, Anna Smed-Sörensen. Depletion of CD16+ monocytes and activation during Puumala orthohantavirus caused HFRS associates with disease severity. *Equal contribution. [Manuscript]