02863nas a2200385   4500000000100000008004100001260001600042653002600058653001800084653002100102653001200123653003300135653001600168100000900184700001100193700001100204700001000215700001100225700001100236700001000247700001000257700001100267700001000278700001000288700001000298700001400308700001000322700001200332245012300344856007500467300000900542490000800551520190400559022001402463       2024                            d  bElsevier BV10aInfectious granulomas10aImmunotherapy10aBacterial burden10aLeprosy10aSingle-cell multimodal omics10aMyobacteria1 aMi Z1 aWang Z1 aWang Y1 aXue X1 aLiao X1 aWang C1 aSun L1 aLin Y1 aWang J1 aGuo D1 aLiu T1 aLiu J1 aModlin RL1 aLiu H1 aZhang F00aCellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics  uhttps://www.thelancet.com/action/showPdf?pii=S2352-3964%2824%2900378-5  a1-190 v1083 a<p><strong>Background:</strong> Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host–pathogen interactions.</p>

<p><strong>Methods: </strong>We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings.</p>

<p><strong>Findings:</strong> Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8+ T cells, and high RGS1 expression in CD8+ T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG+ CD8+ T cells (CD8+ Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8+ Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited antiinflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes.</p>

<p><strong>Interpretation: </strong>The state of IL1B macrophages and functional CD8+ T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria.</p>
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