Resident CD163 macrophages lost during blood-stage infection had not returned months later, and the cells that replaced them were less specialised.

The spleen filters blood, and in malaria it is the organ doing most of the work. Infected red blood cells are stiffer and less deformable than healthy ones, and the spleen is where they are recognised and removed, which is why it enlarges during infection and why splenic function matters for how severe the disease becomes.

A study in Immunity from the University of Bonn and the Peter Doherty Institute for Infection and Immunity in Melbourne reports that this work comes at a lasting cost. In mice, a single episode of blood-stage malaria caused a loss of a specialised population of splenic macrophages that had not recovered months after the infection subsided.

The work was co-led by Professor Elvira Mass of the Life & Medical Sciences Institute at the University of Bonn, who heads the Developmental Biology of the Immune System group, and Dr Lynette Beattie of the Doherty Institute.

Two kinds of macrophage

The finding depends on a distinction that has reshaped immunology over the past fifteen years, and Mass set it out plainly.

“Macrophages essentially come in two different kinds: resident ones, which develop in the embryo, and recruited ones, which can be newly formed at any time,” she said.

Tissue-resident macrophages were long assumed to be replenished continuously from blood monocytes. They are not: many are established before birth, maintain themselves locally, and acquire highly tissue-specific functions over a lifetime in one organ. A resident macrophage in the spleen is a different cell from a monocyte that arrived yesterday, even if both are macrophages.

The cells at issue here are CD163-positive red pulp macrophages, the population responsible for clearing red blood cells and recycling the iron inside them.

Replacement is not restoration

After infection, bone-marrow-derived cells do arrive to fill the gap, and the study’s central result is that they are not equivalent.

“People used to assume that this replacement was virtually 1:1, but our latest research shows this not to be the case,” Mass said.

The replacement cells do not reach the same level of specialisation as the originals. The spleen ends up with macrophages in roughly the right place doing a less refined version of the job — which is a different kind of damage from simply having fewer cells, and harder to detect by counting.

That the deficit matters was shown by removing the cells directly. Depleting CD163 macrophages made malaria more severe, released more parasites into the bloodstream and prolonged anaemia — the three outcomes you would expect if the population responsible for clearing infected red cells is missing.

Structural damage, not just cell loss

The second finding concerns the spleen’s architecture. The marginal zone — the boundary region where blood-borne material is sampled and immune cells are organised — depends on signalling between cell populations, including the marginal metallophilic macrophages that the paper’s title pairs with CD163 cells.

“This structure helps to make sure that the immune cells in the spleen can get the signals that they need to fight bacteria and viruses, and we found that this structure and the associated communication network is persistently damaged by malaria,” Beattie said.

That reframes the result. A spleen that has had malaria is not only worse at handling malaria again — the prognosis for repeat infections was worse — but potentially worse at the general task of mounting responses to blood-borne pathogens, because the structure those responses run through has been disrupted.

“Our results indicate that a single malaria episode can leave a lasting impression on the immunological memory, particle filtering and the spleen’s iron metabolism,” Mass said.

Why it would matter in people

The authors believe a similar change occurs in human spleens, and suggest it may bear on vaccine effectiveness.

The reasoning is worth spelling out, because it points at a real puzzle. Malaria vaccines have been persistently disappointing, with efficacy well below what is achieved against most other pathogens, and immunity after natural infection builds slowly and incompletely over years of repeated exposure. If each episode degrades the splenic architecture through which antibody responses are organised, that would be one mechanism for why protection accumulates so poorly in exactly the populations most exposed.

It would also imply an ordering problem for vaccination campaigns: a vaccine given to a child who has already had several malaria episodes may be working in a spleen less able to respond than the one the trial data were generated in.

Mice, and no numbers

Two limits need stating clearly, and the release states neither.

This is a mouse study throughout. Rodent malaria models use different Plasmodium species from the ones that infect humans, and the spleen’s role differs between them; the suggestion that the same thing happens in human spleens is explicitly a belief about the translation, not a finding. Human splenic tissue is difficult to obtain, which is why this question has been hard to settle.

The release also reports no quantitative results at all — no proportion of CD163 macrophages lost, no time to the follow-up that found no recovery beyond “months”, no effect size for the depletion experiments. “Not the same level of specialisation” is a conclusion from transcriptional or functional data that the release does not show.

What remains is a well-posed hypothesis with a mechanism attached. The useful claim is narrower than the headline and more interesting than it sounds: resident macrophage populations may not be the renewable resource they were assumed to be, and an infection that forces the spleen to work hard may spend something that is not fully refundable.

The study was funded by the Boehringer Ingelheim Foundation, the ImmunoSensation3 Cluster of Excellence at the University of Bonn, the IRTG 2168 Research Training Group and a Global Fund at the TRA Life and Health. The release does not give the full author list, and states no conflicts of interest.

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Notes

1. “CD163+ red pulp macrophages interact with marginal metallophilic macrophages during blood-stage malaria to maintain splenic architecture.” Immunity, 2026. DOI: 10.1016/j.immuni.2026.07.006.
2. University of Bonn. “Malaria causes permanent damage to phagocytes in the spleen.” EurekAlert!, 4 August 2026. https://www.eurekalert.org/news-releases/1138760.

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