Kulikauskaite, Justina; (2022) Origin, infection history, and lung-specific imprints shape phenotype and function of monocyte-derived alveolar macrophages. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Humans are constantly exposed to various lung pathogens. Although most infected people experience mild symptoms, pandemics, such as those caused by influenza A virus (IAV) or SARS-CoV-2, can result in millions of severe cases. This thesis focuses on alveolar macrophages (AMs), a population comprised of embryonically- derived tissue-resident cells (ResAMs) that, following infection and other lung insults, can be partially replaced by monocyte-derived cells (MoAMs) with unique functions for a prolonged time. Here I demonstrated that first, highly immunoreactive post-flu MoAMs initially differed from naive or post-flu ResAMs in their transcriptional profile, but that over time these differences were progressively attenuated. Analysis of the MoAM chromatin landscape suggested transcription factors potentially driving these changes. Second, I investigated how prior monocyte identity and additional functional modifications during the monocyte recruitment stage contributed to the MoAM phenotype. To this end, I showed that early monocyte recruitment was crucial to establishing a stable MoAM population found at one month, and that MoAM immunoreactivity differed depending on the initial lung insult. I also demonstrated that early post influenza infection, increased proportion of monocytes with changed phenotype were produced in the bone marrow and entered the blood. Finally, when fighting a subsequent S. pneumoniae challenge, post flu lungs contained MoAMs with limited phagocytic capacity, and neutrophil recruitment into the alveolar space was increased. This work demonstrates how a single lung insult drives both short-term functional changes in monocytes, but also leads to the establishment of a new population of monocyte-derived AMs with prolonged phenotypic differences to ResAMs. Consequently, post insult lungs employ changed defence strategies against subsequent unrelated infections, with lower initial phagocytosis but accelerated neutrophil recruitment. These findings have major implications for humans, as sequential respiratory infections could lead to changes in peripheral monocytes and monocyte-derived AMs in the lung.

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