Review Recent Advances on the Innate Immune Response to Coxiella burnetii, 2021, Sireci et al

[Hutan]

Recent Advances on the Innate Immune Response to Coxiella burnetii
Guido Sireci, 1 Giusto Davide Badami, 1 Diana Di Liberto, 1 Valeria Blanda,

2 , * Francesca Grippi, 2 Laura Di Paola, 2Annalisa Guercio, 2 José de la Fuente, 3 , 4 and Alessandra Torina 2

Abstract
Coxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of a worldwide zoonosis known as Q fever. The pathogen invades monocytes and macrophages, replicating within acidic phagolysosomes and evading host defenses through different immune evasion strategies that are mainly associated with the structure of its lipopolysaccharide. The main transmission routes are aerosols and ingestion of fomites from infected animals. The innate immune system provides the first host defense against the microorganism, and it is crucial to direct the infection towards a self-limiting respiratory disease or the chronic form.

This review reports the advances in understanding the mechanisms of innate immunity acting during C. burnetii infection and the strategies that pathogen put in place to infect the host cells and to modify the expression of specific host cell genes in order to subvert cellular processes. The mechanisms through which different cell types with different genetic backgrounds are differently susceptible to C. burnetii intracellular growth are discussed. The subsets of cytokines induced following C. burnetii infection as well as the pathogen influence on an inflammasome-mediated response are also described.

Finally, we discuss the use of animal experimental systems for studying the innate immune response against C. burnetii and discovering novel methods for prevention and treatment of disease in humans and livestock.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593175/

 

[Hutan]

I'm part the way through this relatively recent review paper, and I'm finding it interesting, especially in the light of recent findings from Long Covid studies, such as the possibility that interferons and infected monocytes play a role in post-infection syndromes.

I think the fact that so many of the infections that seem to trigger ME/CFS-like disease have been shown to be able to persist in cells is a clue.

C. burnetii has two forms, the small cell variant and the large cell variant. The small cell variant can exist in an acidic lysosome in a cell, with genes activated that reduce cell wall shedding, to reduce its detection by immune detectors inside the cell.


C. burnetii also varies in the nature of its cell wall (LPS) - there's a reference to phase 1 and phase 2 versions. The difference seems to be important for chronicity. I'm not fully understanding when and where these phases come into play and the consequences of each.

Phase variation is also used in the diagnosis of Q fever since during acute Q fever, C. burnetii induces antibodies against phase II (protein antigens), while chronic Q fever, often manifested as endocarditis, is associated with the production of high titers of antibodies directed against phase I (LPS antigen)

The overproduction of TNF stimulated by avirulent C. burnetii is probably related to the increase in bacterial binding to monocytes and not to the potency of their LPS (Dellacasagrande et al., 2000b), even considering that the interaction of avirulent variants with monocytes was dramatically more efficient than that of virulent organisms (Capo et al., 1999b).

This 1998 finding of increased IFN-y in people with QFS seems important, given the recent finding of this in a subset of people with post-Covid symptoms:

For example, PBMCs from patients affected by Q fever Fatigue Syndrome (QFS), a debilitating fatigue syndrome lasting 5 to 10 years or longer after the acute illness, showed increased IL-6 and IFN-gamma and reduced IL-2 levels compared to controls (Penttila et al., 1998).

Here's a comment on the Raijmaker paper about the possibility of an infection causing epigenetic remodelling relevant to QFS:

It has been proposed that acute C. burnetii infection may cause an epigenetic remodeling of the promoter regions of pro-inflammatory cytokine genes, which determines an impaired inflammatory response. In particular, QFS patients affected by frequent and severe infections in the upper respiratory tract show a reduced cytokine response, probably due to a long-term change in monocytes induced by C. burnetii(Raijmakers et al., 2019).

 

[Hutan]

On interferons:

It is reported that IFN-y levels are not increased in chronic Q-fever patients, and that 'QFS patients showed similar levels of IFN-y' as those affected by chronic Q fever. So those two reported facts suggests that IFN-y levels are not higher in QFS than in healthy people - which is different to what was reported just above from the 1998 paper. I guess it would be necessary to go to the original papers and check.

In Q fever, IFN-γ promotes C. burnetii killing by the induction of TNF-mediated apoptosis in infected monocytes (Dellacasagrande et al., 1999; Dellacasagrande et al., 2002). In particular, IFN-γ is significantly increased in acute but not in vascular chronic Q fever patients compared to people with past infection, whereas IL-18 shows a similar rise in both acute and chronic patients. The IFN-γ-inducible protein 10 (IP-10) and the TGF-β instead are lower in patients affected by chronic vascular infection, suggesting that chronic patients had an impaired Type I immune response against C. burnetii (Pennings et al., 2015).

Patients affected by chronic Q fever showed intact IFN-γ response, so defects concerning this pathway are not involved in progression to chronic infection. Instead, since polymorphisms in the IL-12p40 gene are associated with chronic Q fever, the IL-12/IFN-γ pathway may play a role in this progression (Schoffelen et al., 2017). The QFS patients show similar levels of IFN-γ and decreased IFN-γ/IL-2 ratio compared to those affected by chronic Q fever. Symptom duration is positively correlated with IL-2 production and negatively correlated with the IFN-γ/IL-2 ratio, suggesting an impaired cell-mediated response in QFS (Keijmel et al., 2016).

Type 1 interferons are discussed but not in the context of QFS:

Type I IFNs (IFN-α, β, κ, ω, τ, and ϵ) and other interferons are important in immune response against C. burnetii (Snyder et al., 2017)

 

[Hutan]

On apoptosis:

C. burnetii, as other intracellular pathogens, need to hinder the apoptosis process to survive and to establish a favorable environment inside the host cell. It has been seen that cells infected by C. burnetii show different susceptibility to apoptosis depending on their type, stage of maturation, and surface receptors expressed (Schoenlaub et al., 2016). For example, infection by NM II C. burnetii in murine bone marrow neutrophils inhibits apoptosis (Cherla et al., 2018), whereas in peritoneal B1a cells from the same species, it induces cell death (Schoenlaub et al., 2016

That suggests the bacteria can infect neutrophils in bone marrow and extend the life of the host cells.

There's a couple of references given for the existence of QFS as a thing:

Moreover, patients returning from C. burnetii acute infection can develop a chronic fatigue syndrome (Wildman et al., 2002; Morroy et al., 2016).

and some comment on the persistence of Coxiella cell components long after an acute infection that are able to induce an abnormal immune response:

Some studies (Marmion et al., 2009; Sukocheva et al., 2010) performed by inoculating SCID mice with samples (bone marrow, PBMC, or heart valve) coming from Q fever patients showed the persistence of the so-called “Immunomodulatory complex” (IMC) even after a long time away from acute infection. This is composed by non-infective and non-biodegraded Coxiella cell components, including C. burnetii antigens, specific LPS, and traces of genomic DNA. The persistence of the IMC involve the capacity to pass repeatedly into the macrophages, and it induces an abnormal immune response, which may explain the development of chronic sequelae as the long fatigue syndrome after the acute infection in some patients.