Spatial Metabolomic Mapping of Long COVID Tissues Using MALDI Mass Spectrometry Imaging

Project Summary

This project applies matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to identify molecular changes within tissues from people with Long COVID. The technology can simultaneously map hundreds of lipids and metabolites at cellular resolution while preserving their spatial relationship to sites of inflammation, oxidative stress, mitochondrial dysfunction, and pathogen persistence.

The team is analyzing colorectal tissue, bone marrow, muscle, cerebrospinal fluid, and paired blood or plasma samples collected through the UCSF LIINC cohort and PolyBio-supported studies. These include samples from people with Long COVID, carefully matched fully recovered controls, and participants in interventional clinical trials.

MALDI MSI findings will be integrated with spatial multiomic analyses performed on adjacent tissue sections, including tests for single- and double-stranded SARS-CoV-2 RNA and digital spatial profiling of viral–immune–host interactions. The resulting molecular maps can reveal localized metabolic signatures consistent with impaired mitochondrial energy production, altered lipid metabolism, and oxidative stress. The investigators will also examine whether MALDI MSI can detect and characterize extracellular vesicles in paired plasma and cerebrospinal fluid samples. By connecting tissue-level molecular abnormalities with potentially accessible biofluid signals, the project may identify biomarkers for patient stratification and treatment-response monitoring.

Project Background

Long COVID is associated with abnormalities in immune signaling, energy metabolism, oxidative stress, lipid regulation, and mitochondrial dysfunction. However, most studies analyze molecules extracted from blood or homogenized tissue, eliminating the spatial information needed to determine where these changes occur and how they relate to infected cells, inflammatory microenvironments, or specific tissue structures.

MALDI MSI addresses this limitation by measuring many molecular species directly within intact tissue sections. A chemical matrix is applied to the tissue and stimulated with a laser, enabling endogenous molecules to be ionized, identified by mass spectrometry, and mapped back to their original locations. The approach is label-free and does not require investigators to select a limited set of molecular targets in advance. Because mitochondrial dysfunction can produce characteristic changes in metabolites and membrane lipids, MALDI MSI may identify spatial molecular signatures of disrupted mitochondrial activity within affected tissues.

The Neumann laboratory recently demonstrated the capabilities of this platform by using MALDI trapped-ion mobility mass spectrometry imaging to localize polystyrene particles across mouse tissues while simultaneously identifying organ-specific lipid remodeling associated with exposure. The study detected distinct metabolic changes in the stomach, liver, and heart, demonstrating that MALDI MSI can spatially connect a low-abundance exposure with its surrounding biochemical effects. Read the team’s paper in Angewandte Chemie.

In this project, the team expects to detect approximately 200 distinct lipids and 150 metabolites in each tissue sample. These unbiased molecular maps will be aligned with measurements of SARS-CoV-2 RNA, immune activity, and host responses from contiguous tissue sections. This integrated analysis will test whether persistent viral material is associated with localized metabolic dysfunction, including molecular signatures consistent with altered mitochondrial energy metabolism, and identify biochemical pathways that may contribute to Long COVID pathology.