Tag Archives: Pathophysiology

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of …

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of the world’s population. RA happens when a person’s own antibodies attack joint tissue, causing painful swelling, stiffness, and redness. Some research has suggested that there is a link between RA and gum disease.

Image credit: Pixabay

Gum disease is estimated to affect up to 47 percent of adults, and in the disorder, oral microbes can move to the blood after the gums start to bleed. An increase in disease activity has been observed in RA patients who also have gum disease. Gum disease has been shown to be more common in RA patients who carry a certain type of antibodies, called anti-citrullinated protein antibodies (ACPAs), though ACPAs are often found in the blood of individuals with RA. The presence of ACPAs can often predate the diagnosis of RA by a few years.

A new study investigated the connections between these observations. In this work, the researchers collected blood samples from a small group of ten people with RA, five with and five without gum disease. These samples were collected every week for one year, and the investigators assessed the expression of both human and bacterial genes in those samples.

Certain types of inflammatory immune cells carried gene expression signatures that were associated with the autoimmune flares of arthritis patients who also had periodontal disease, as well as the presence of certain oral bacteria in the blood.

Many of these oral bacteria were chemically altered by deimination; they were citrullinated. Citrullination can change the structure and function of proteins. Although citrullination can be a part of the normal function of tissues, high levels of citrullination have been linked to inflammation.

Citrullination can also create targets for ACPAs; when the normal, unconverted forms of the oral bacteria were incubated with ACPAs, the antibodies did not react, but when the citrullinated oral bacteria were exposed to ACPAs, there was a reaction. ACPAs appear to be bound to oral microbes in RA patients.

The findings have been reported in Science Translational Medicine.

The study noted that the immune response to oral microbes could be influencing RA flares, that oral microbes can trigger a specific antibody reaction in patients with both RA and gum disease, and that RA flares cause varying immune signatures, which could reflect different flare triggers.

It could be that gum disease repeatedly causes the immune system to respond, and as the immune system keeps reacting and repeatedly increasing inflammation, RA may eventually begin to emerge. More work will be needed, however, to fully understand whether gum disease is playing a causative role in the development of RA.

Source: Science Translational Medicine

Carmen Leitch

Long COVID still affects many people who had a case of COVID-19; even people who had mild cases …

Long COVID still affects many people who had a case of COVID-19; even people who had mild cases and were not hospitalized are at risk for the chronic disorder. Scientists and clinicians are still learning about the illness, which causes a wide range of symptoms and happens for unknown reasons. There are several hypotheses, however, and the disorder may also arise in different people for different reasons. New research has suggested that long COVID happens because particles of SARS-CoV-2, the virus that causes COVID-19, hide away in parts of the body, and the immune system becomes overactivated trying to eliminate them. The study has been reported in PLOS Pathogens.

Colorized scanning electron micrograph of a cell (brown) infected with the Omicron strain of SARS-CoV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Symptoms of long COVID can include fatigue, brain fog, cough, shortness of breath, and chest pain, and these symptoms last more than four weeks after the acute phase of COVID-19. The illness is thought to impact about 20 percent of people who get COVID, noted Brent Palmer, Ph.D., an associate professor at the University of Colorado School of Medicine.

In this study, the researchers followed forty COVID-19 patients; twenty of them totally eliminated the infection and twenty developed long COVID, also known as  post-acute sequelae of COVID (PASC). The investigators used blood and stool samples from the study volunteers to identify T cells that were specific to COVID-19 and remained active after the initial infection was over.

These cells were then incubated with bits of the virus, and the scientists were able to see how frequently CD4 and CD8 T cells were reacting by generating cytokines. They found that long COVID patients carried levels of cytotoxic CD8 T cells that were as much as 100 times higher compared to people who cleared the infection.

Palmer also studies HIV infection, and he was astonished to find that about 50 percent of T cells were still directed against COVID-19 six months after their initial infection. “That’s an amazingly high frequency, much higher than we typically see in HIV, where you have ongoing viral replication all the time,” he added. “These responses were in most cases higher than what we see in HIV.”

CU pulmonologist Sarah Jolley, MD was a study co-author who obtained pulmonary data for the study volunteers. The researchers found that pulmonary function decreased as the level of COVID-19-specific T cells increased.

“That showed a really strong connection between these T cells that were potentially driving disease and an actual readout of disease, which was reduced pulmonary function. That was a critical discovery.”

The researchers have suggested that long COVID is drive by the immune system, which is increasing inflammation as it attempts to remove residual SARS-CoV-2 particles that cannot be detected with a nasal swab, but nonetheless remain. Palmer noted that some autopsies of COVID-19 patients have revealed the virus in many organs including the lungs, gut and kidney.


Additional work by Palmer and colleagues was reported in the journal Gut; this study indicated that the composition of the gut microbiomes of long COVID patients reflects an elevation of inflammatory markers. There may also be a link between the gut microbiome and the inflammation that is observed in long COVID, noted the researchers.

Palmer added that some studies have shown that antiviral medications like Paxlovid, or doses of vaccine may help relieve the symptoms of long COVID patients. This may happen because their immune systems are being given enough of a stimulatory bump to finally remove the infection, and it would show that a hidden reservoir of virus likely exists in these patients.

Sources: CU Anschutz Medical Campus, PLOS Pathogens, Gut

Carmen Leitch

Even after decades of research, the cause of the most common form of dementia, Alzheimer’s disease, is unclear. …

Even after decades of research, the cause of the most common form of dementia, Alzheimer’s disease, is unclear. Evidence that pointed to plaques and tangles of disordered proteins called amyloid beta and tau has been called into question since therapeutics that aim at the protein clumps have not been particularly effective at relieving disease. In recent years, scientists have also found evidence that viral infections may be to blame for some serious long-term diseases; multiple sclerosis, for example, seems to only develop in people who have been infected with Epstein-Barr virus (EBV). The pandemic coronavirus SARS-CoV-2 also appears to have neurological impacts in some people.

Influenza B virus particles, colorized blue, isolated from a patient sample and then propagated in cell culture. Both influenza A and B can cause seasonal flu; however, unlike influenza A virus, which can also infect animals, influenza B only infects humans. Microscopy by John Gallagher and Audray Harris, NIAID Laboratory of Infectious Diseases. Credit: NIAID

Researchers have now used the power of biobanks that contain health data from hundreds of thousands of people to look for links between viral infections like influenza and EBV and neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), generalized dementia, and Parkinson’s disease. Data from FinnGen on over 300,000 people was used to look for associations that were then assessed in the nearly half a million people in the UK Biobank for confirmation. An additional cohort of almost 100,000 people who had not had any neurodegenerative disorder was used as a control group. COVID-19 hospitalizations were not included in this study. The findings have been reported in Neuron.

The research showed that there is a connection between viral infections and neurodegeneration, which is particularly significant for viruses that are able to cross the blood brain barrier and infect the central nervous system, perhaps unsurprisingly. The study authors suggested that these so-called neurotropic viruses may be causing neurodegeneration because of neuroinflammation.

A first pass of the data suggested there were 45 significant associations between viral infections and neurodegenerative disease. After querying the UK Biobank, the researchers refined it to 22 associations.

The top candidate was generalized dementia, which was linked to infections with six different viruses: all influenza, flu and pneumonia, viral pneumonia, viral encephalitis, viral warts, and other viral diseases seem to raise the risk of generalized dementia. The research also showed that anyone who had viral encephalitis was 20 times more likely or more to receive an Alzheimer’s diagnosis compared to people who have not had viral encephalitis.

Severe flu was connected to a greater likelihood of different types of neurodegeneration. Influenza and pneumonia exposures were also linked to an increased risk of all neurodegenerative disorders except multiple sclerosis.

Senior study author Michael Nalls, Ph.D., the NIH Center for Alzheimer’s Related Dementias (CARD) Advanced Analytics Expert Group leader, also noted that the viral infections that are being considered in this study were quite severe and led to hospitalizations; they were not mild cases of the common cold.

“Nevertheless, the fact that commonly used vaccines reduce the risk or severity of many of the viral illnesses observed in this study raises the possibility that the risks of neurodegenerative disorders might also be mitigated,” said Nalls.

“Our results support the idea that viral infections and related inflammation in the nervous system may be common and possibly avoidable risk factors for these types of disorders,” added study co-author Andrew B. Singleton, Ph.D., the director of CARD.

Sources: National Institutes of Health, Neuron

Carmen Leitch

New research evaluates clinical trials investigating post-acute COVID-19 syndrome treatment

In a recent article published in Clinical Microbiology and Infection, researchers reviewed all registered trials currently investigating potential treatment options for post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS).

Additionally, the scientists examined the limitations of the current clinical trials to inform future research.

Study: A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Image Credit: GoodStudio/Shutterstock
Study: A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Image Credit: GoodStudio/Shutterstock


Over 663 million people contracted COVID-19 globally, of which 10% to 20% suffered from PACS, a complex systemic post-COVID-19 disease with substantial morbidity, per the World Health Organization (WHO) COVID-19 dashboard. Though studies have identified over 100 persistent symptoms associated with COVID-19, most studies have documented fatigue, followed by dyspnea, as the most reported PACS symptom.

There is a shortage of medical interventions to treat PACS patients. The data indicate that PACS patients will continue to spike globally in the coming future, increasing the burden on healthcare facilities. With just four multi-center clinical trials in the pipeline, there is an urgent need for more research investigating potential therapeutic options for PACS.

About the study

In the present study, researchers screened the WHO Internal Clinical Trials Registry Platform (ICTRP) on September 16th, 2022, to identify PACS trial registry entries. The ICTRP gathers records from 17 trial registries collecting information globally.

For trial selection, they adhered to the Patient Intervention Comparison Outcomes Study type (PICOS) framework, which mandated any patient sample size with patients of any age diagnosed with COVID-19 and related persistent symptoms for over four weeks or PACS. Additionally, these trials mentioned treatment of PACS, not prevention, and covered any outcome.

In total, 12 reviewers extracted data from the selected trials in duplicate and reviewed them as per the PRISMA guidelines. Later, two reviewers merged the overlapping primary outcomes and grouped them into appropriate outcome domains. Further, they used experimental arm(s) to identify all interventions under investigation for PACS for each trial. Furthermore, the team recorded trial numbers, patients enrolled, nations, and their specific clinical use per the trial source for each intervention under investigation. Finally, they organized all interventions into different classes, sorted into seven human organ systems. Also, they used the WHO definition to organize interventions under the rehabilitation classes. They used percentages to summarize trial characteristics.

Study findings

The study identified 388 trials exploring 144 interventions for PACS. From all, 108 and 133 clinical trials specifically targeted fatigue and the pulmonary system, respectively. Among the interventions targeting a single human organ system, most were not specific to an organ system, and 70 trials adopted an all-inclusive approach to weaken PACS symptoms. It raises the issue of the reproducibility of these trials and the efforts to determine their clinical benefits later.

Further, the researchers noted that most trials investigated PACS treatment strategies repurposed from similar conditions; for instance, the rehabilitation interventions are currently exploring treatment strategies for cancer-related fatigue syndrome.

In addition, most interventions targeted multiple PACS symptoms concurrently or proposed the same intervention for different symptoms. Furthermore, these trials investigated barely a few novel therapeutic agents specifically for PACS (e.g., RSLV-132, AXA1125).

The clinical category of the patient, in or outpatient, admitted to the intensive care unit (ICU) under treatment is crucial. However, over 60% of these trials barely indicated the hospitalization status of the trial population in their inclusion/exclusion criteria.

Most importantly, all the included trials used a different PACS definition. So, the researchers noted a considerable heterogeneity among the included trials in this aspect, and the reported primary outcomes were also often not standardized. Additionally, they did not refer to time zero, with around 66 clinical trials mentioning PACS patients as having a positive and then a negative COVID-19 test. It made it difficult to ascertain whether the patient trial population recovered from COVID-19 exhibited PACS symptoms.

The cohort size of almost three-fourths of the trials was under 100. Moreover, over one-third of the participants were open-label. Accordingly, several interventions reported in these trials likely yielded only preliminary evidence of the safety and effectiveness of the PACS treatment options. Additionally, these trials used subjective and patient-reported scales that increased the risk of outcome assessment bias.


To conclude, the study highlighted the issue of the need for proper diagnostic tests for PACS, which hindered the systematic identification of patients with PACS and the assembling of a control group. Remarkably, of the four international multi-center trials, two trials neither explicitly mentioned PACS nor defined a time reference. A clinical trial mentioned PACS patients but did not define a time reference.

Moreover, many registered trials needed to have more effectively defined their inclusion criteria. They did not indicate the acute phase of illness, which made it impossible to ascertain whether all the included patients were experiencing symptoms due to some other chronic/infectious diseases (e.g., post-intensive care syndrome) or PACS.

The healthcare demands of PACS patients will continue to rise. Thus, there is an urgent need for robust PACS treatment research with standardized outcome reporting adhering to WHO’s recommendations. Data from the current study could inform future PACS research for developing robust treatment options. Though repurposing existing treatments could work, for now, the focus should be on developing novel therapies, specifically targeting PACS pathophysiology. In this regard, International collaborations, such as the National Institutes of Health’s RECOVER initiative for PACS, should be encouraged.

Furthermore, it is crucial to include trials investigating alternative medicine, which currently has low registration quality. The authors also advocated improving the quality of research protocols reporting and sharing them for public access. All these endeavors could greatly benefit all the handlers of clinical trial evidence, including PACS patients.

Journal reference:
  • Nader A. Fawzy, Bader Abou Shaar, RandM. Taha, Tarek Z. Arabi b, Belal N. Sabbah, Mohamad S. Alkodaymi, Osama A. Omrani, Tariq Makhzoum, Najwa E. Almahfoudh, Qasem A. Al-Hammad, Wed Hejazi, Yasin Obeidat, Naden Osman, Khaled M. Al-Kattan, Elie F. Berbari, Imad M. Tleyjeh. (2023). A Systematic Review of Trials Currently Investigating Therapeutic Modalities for Post-Acute COVID-19 Syndrome and Registered on World Health Organization International Clinical Trials Platform. Clinical Microbiology and Infection. doi: https://doi.org/10.1016/j.cmi.2023.01.007 https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(23)00009-5/fulltext

What are the major findings of long COVID research?

In a recent review published in Nature Reviews Microbiology, researchers explored existing literature on long coronavirus disease (COVID). They highlighted key immunological findings, similarities with other diseases, symptoms, associated pathophysiological mechanisms, and diagnostic and therapeutic options, including coronavirus disease 2019 (COVID-19) vaccinations.

Study: Long COVID: major findings, mechanisms and recommendations. Image Credit: Ralf Liebhold/Shutterstock
Study: Long COVID: major findings, mechanisms and recommendations. Image Credit: Ralf Liebhold/Shutterstock

Long COVID refers to a multisystemic disease among SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)-positive individuals, with increasing prevalence rates by the day. Studies have reported on long COVID risk factors, symptoms, pathophysiology, diagnosis, and treatment options, with increasing similarities between long COVID and other diseases such as POTS (postural orthostatic tachycardia syndrome) and ME/CFS (myalgic encephalomyelitis/ chronic fatigue syndrome).

About the review

In the present review, researchers explored the existing data on long COVID immunology, symptoms, pathophysiology, diagnosis, and therapeutic options.

Key long COVID findings and similarities with other diseases

Studies have reported persistently reduced exhausted T lymphocytes, dendritic cells, cluster of differentiation 4+ (CD4+) lymphocyte and CD8+ lymphocyte counts, and greater PD1 (programmed cell death protein-1) expression. In addition, increase in innate cell immunological activities, non-classical monocytes, expression of interferons (IFNs)-β, λ1, and interleukins (IL)-1β, 4,6, tumor necrosis factor (TNF). Cytotoxic T lymphocyte expansion has been linked to gastrointestinal long COVID symptoms, and persistent increase in CCL11 (C-X-C motif chemokine 11) expression has been linked to cognitive dysfunction among long COVID patients.

Elevated autoantibody titers have been reported among long COVID patients, such as autoantibodies against ACE2 (angiotensin-converting enzyme 2), angiotensin II receptor type I (AT1) receptors, β2-adrenoceptors, angiotensin 1–7 Mas receptors, and muscarinic M2 receptors. Reactivation of Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6) has been reported in long COVID patients and ME/CFS. EBV reactivation has been linked to neurocognitive impairments and fatigue in long COVID.

SARS-CoV-2 persistence reportedly drives long COVID symptoms. SARS-CoV-2 proteins and/or ribonucleic acid (RNA) have been detected in cardiovascular, reproductive, cranial, ophthalmic, muscular, lymphoid, hepatic, and pulmonary tissues, and serum, breast, urine, and stool obtained from long COVID patients. Similar immunological patterns are noted between long COVID and ME/CFS, with elevated cytokine levels in the initial two to three years of disease, followed by reduction with time, without symptomatic improvements in ME/CFS. Lower cortisol levels, mitochondrial dysfunction, post-exertional malaise, dysautonomia, mast cell activation, platelet hyperactivation, hypermobility, endometriosis, menstrual alterations, and intestinal dysbiosis occur in both conditions.

Long COVID symptoms and underlying pathophysiological mechanisms

Long COVID-associated organ damage reportedly results from COVID-19-induced inflammation and associated immune responses. Cardiovascular long COVID symptoms such as chest pain and palpitations have been associated with endothelial dysfunction, micro-clotting, and lowered vascular density. Long COVID has been associated with an increased risk of renal damage and type 2 diabetes. Ophthalmic symptoms of long COVID, including altered pupillary responses to light, result from the loss of small nerve fibers in the cornea, increased dendritic cell density, and impaired retinal microvasculature. Respiratory symptoms such as persistent cough and breathlessness result from altered pulmonary perfusion, epithelial injury, and air entrapment in the airways.

Cognitive and neurological long COVID symptoms include loss of memory, cognitive decline, sleep difficulties, paresthesia, balancing difficulties, noise and light sensitivity, tinnitus, and taste and/or smell loss. Underlying pathophysiological mechanisms include kynurenine pathway activation, endothelial injury, coagulopathy, lower cortisol levels, loss of myelin, microglial reactivation, oxidative stress, hypoxia, and tetrahydrobiopterin deficiency.  Gastrointestinal symptoms such as pain in the abdomen, nausea, appetite loss, constipation, and heartburn have been associated with elevated Bacteroides vulgatus and Ruminococcus gnavus counts and lower Faecalibacterium prausnitzii counts. Neurological symptoms often have a delayed onset, worsen with time and persist longer than respiratory and gastrointestinal symptoms, and long COVID presents similarly in children and adults.

Diagnostic and therapeutic options for long COVID, including COVID-19 vaccines

The diagnosis and treatment of long COVID are largely symptom-based, including tilt tests for POTS, magnetic resonance imaging (MRI) to detect cardiovascular and pulmonary impairments, and electrocardiograms to detect QRS complex fragmentation. Salivary tests and serological tests, including red blood cell deformation, lipid profile, complete blood count, D-dimer, and C-reactive protein (CRP) evaluations, can be performed to assess immunological biomarker levels. PCR (polymerase chain reaction) analysis is used for SARS-CoV-2 RNA detection and quantification, and antibody testing is performed to assess humoral immune responses against SARS-CoV-2.

Pharmacological treatments include intravenous Ig for immune dysfunction, low-dosage naltrexone for neuronal inflammation, beta-blockers for POTS, anticoagulants for microclot formation, and stellate ganglion blockade for dysautonomia. Other options include antihistamines, paxlovid, sulodexide, and pycnogenol. Non-pharmacological options include cognitive pacing for cognitive impairments, diet limitations for gastrointestinal symptoms, and increasing salt consumption for POTS. COVID-19 vaccines have conferred minimal protection against long COVID, the development of which depends on the causative SARS-CoV-2 variant, and the number of vaccination doses received. Long COVID has been reported more commonly post-SARS-CoV-2 Omicron BA.2 subvariant infections.

Based on the review findings, long COVID is a multiorgan disease that has debilitated several lives worldwide, for which diagnostic and therapeutic options are inadequate. The findings underscored the need for future studies, clinical trials, improved education, mass communication campaigns, policies, and funding to reduce the future burden of long COVID.

Journal reference:

Fungi that can cause lung infections are all over our environment. Recent research has highlighted the spread of …

Fungi that can cause lung infections are all over our environment. Recent research has highlighted the spread of fungal species as well. Once confined to certain regions, several fungal pathogens are now found all over the United States, for example, and the World Health Organization has warned that fungal infections are a rising threat. While fungi like Aspergillus aren’t harmful to most people, they may cause serious or even deadly infections in those with fragile immune systems. Now, research has found that some viruses, including influenza and SARS-CoV-2 disrupt the body’s ability to fight fungal infections, increasing the risk of disease even in otherwise healthy people. The findings have been reported in Science Translational Medicine.

A medical illustration of an azole-resistant fungus, Aspergillus fumigatus / Credit: CDC/ Antibiotic Resistance Coordination and Strategy Unit / Medical Illustrator: Stephanie Rossow

“We discovered that influenza and COVID-19 destroy a previously unknown natural immunity that we need to resist invasive fungal infections,” said first study author and graduate student Nicole Sarden of the University of Calgary.

In this study, the researchers used a mouse model and samples of human blood and tissue to assess the impact of a viral infection. Normally, white blood cells called neutrophils and a special kind of B cell assemble to battle fungal infections.

The researchers found that neutrophils that were exposed to viruses could detect a fungal infection, and did gather to fight it. But the neutrophils did not move to destroy the fungi and eliminate the infection as expected. The viral particles had also impaired the B cells, making them sluggish and impeding their cooperation with neutrophils. Thus, the white blood cells could not remove the fungal infection.

Additional work revealed, however, that existing drugs can be repurposed; they act to replace the natural antibodies that the impaired B cells would otherwise be making if they had not been impacted by a virus. These drugs enable neutrophils and B cells to team up and fight fungal infections once more, said Sarden.

Senior study author Dr. Bryan Yipp, MD began to work on this project after caring for a young person who had died from influenza-associated aspergillosis; “…every therapy we tried failed,” said Yipp. “Our findings are very timely given the high numbers of patients affected by multiple respiratory viruses including influenza.”

The researchers are hopeful that this study will help scientists create new diagnostic tests that can predict who might be affected by a severe fungal infection, based on their natural antibody levels. Antibody replacement methods might also be tested in clinical trials in the future.

Sources: University of Calgary, Science Translational Medicine

Carmen Leitch

Our immune system has to be able to rapidly mount a response to pathogenic invaders, wounds, and other …

Our immune system has to be able to rapidly mount a response to pathogenic invaders, wounds, and other injuries. But it also has to be carefully controlled. When the body overreacts to an infection, it can cause a condition known as sepsis, which can be deadly. Sepsis is estimated to have caused about 11 million deaths around the world in 2017 alone. Now, scientists are learning more about the immune molecules and cells that trigger sepsis. The findings have been reported Science Immunology.

Image credit: Pixabay

Cytokines are immune signaling molecules. Tumor necrosis factor (TNF) is a widely studied cytokine that has many roles. TNF is activated by a crucial component of bacterial cell walls, called lipopolysaccharide (LPS), and recruits immune cells to fight infection. TNF can aid in the repair of tissue and cell survival, but it also has to be regulated. Overactive TNF signaling has been implicated in inflammatory diseases like rheumatoid arthritis. The uncontrolled production of cytokines, including TNF, can also cause a cytokine storm, a dangerous situation.

There is no standardized definition for a cytokine storm, in part because it can be difficult to define the line between a normal and abnormal immune response. But there are commonly accepted clinical features of cytokine storms, such as fever, headache, fatigue, anorexia, rash, diarrhea, and respiratory symptoms that often progress to more serious problems including, but not limited to catastrophic hemorrhages, shock, hypoxemia, renal failure, or liver damage.

While scientists have developed TNF blockers that have been useful for some autoimmune disorders including rheumatoid arthritis, those drugs don’t prevent cytokine storms that arise in conditions like severe COVID-19 cases or sepsis. The mechanisms of TNF are still not well-understood.

In the new study, researchers induced death in mice from TNF. But when mice did not express either of two proteins that are linked to the immune response to LPS, called TRIF and CD14, survival improved. Previous work has shown that TRIF and CD14 help regulate a protein complex that is related to LPS-induced inflammation and cell death.

Blood cells called myeloid cells are known to produce a lot of TNF. The research also showed that if mice lacked neutrophils and macrophages, two kinds of myeloid cells, symptoms of sepsis were reduced and survival improved when mice were given a lethal dose of TNF. The study authors suggested that macrophages and neutrophils are, therefore, contributing significantly to TNF-mediated death in mice.

It may also be possible to treat sepsis by targeting TRIF and CD14, which could reduce cell death and inflammation.

Sources: New England Journal of Medicine, Medical Xpress via The Conversation, Science Immunology

Carmen Leitch

Powerful imaging tool creates 3D atlas of the spectrum of tuberculous and COVID-19 lung lesions

Gross anatomy reveals three-dimensional shapes of pathology at a large scale. Histology, in contrast, reveals the microscopic anatomy of biological structures. But that magnification comes at a cost -; histology shows only two-dimensional shapes because it studies small, flat slices of stained tissue.

This lack of three dimensions means histology can miss important pathophysiologies in the damaged lungs of patients with tuberculosis, or TB, and COVID-19, the two deadliest infectious diseases of mankind in recent years.

Now researchers report that a powerful imaging tool called microCT can be used to create a three-dimensional, or 3D, atlas of the spectrum of lung lesions in both tuberculosis and COVID-19, at near-microscopic levels. This gives unexpected insights into the unseen microarchitecture of the lesions within the context of the whole lung.

The research, published in the journal EMBO Molecular Medicine -; with one of the 3D images featured on the journal cover, was led by Adrie Steyn, Ph.D., a professor in the Department of Microbiology at the University of Alabama at Birmingham and member of the Africa Health Research Institute, or AHRI, University of KwaZulu-Natal, in Durban, South Africa, along with UAB and AHRI researchers and colleagues at various South African institutions.

To the best of our knowledge, this is the first study to use microCT to elucidate macro- and microscopic features of tuberculosis lesions such as cavitation, calcification and necrosis, as well as COVID-19 pathophysiology across large lung samples in three dimensions. A major new contribution of this study is the characterization of obliterated airways in TB and hemorrhage from ruptured blood vessels in COVID-19 lungs that would not be possible with conventional two-dimensional platforms. Further, microCT analysis of an entire COVID-19 lung lobe in 3D represents a technical advance that enabled us to contextualize vascular pathology within the greater lung architecture and visualize vascular micro-architecture in remarkable detail.”

Adrie Steyn, Ph.D., Professor, Department of Microbiology, University of Alabama at Birmingham

One of the benefits of microCT is creating a 3D image of a lesion. In a tuberculosis paper last year, Steyn and colleagues showed that power. For 70 years, they said, clinicians thought TB granulomas in the lungs of patients were spherical or ovoid because conventional histology showed round features, and researchers intuitively assumed those meant the granulomas were spherical or ovoid. But such round images are similar to cutting a very thin slice through a thick tree branch and assuming the branch is round or oval.

Instead of spheres, the 3D images revealed the larger granulomas as anything but round -; they had complex, branched shapes. One looked somewhat like a ginger root, and another like a cluster of early buds on a cherry tree, before the blossoms appear.

In Steyn’s current study, researchers also identified an unusual spatial arrangement of vasculature within an entire lobe of a COVID-19 lung, and 3D images of blood vessels revealed microangiopathy associated with hemorrhage.

Notably, Steyn says, this imaging of pathological anomalies revealed hidden pathological structures that might have been disregarded, demonstrating a powerful method to visualize pathologies in 3D in TB lung tissue and whole COVID-19 lobes.

The researchers compared microCT with two lower-resolution clinical imaging platforms that do not yield accurate three-dimensional images of TB lesions -; high-resolution computed X-ray tomography, which is used to aid diagnosis of tuberculosis, and low-resolution, low-energy “soft” X-ray CT, commonly used in mammography. MicroCT imaging provides higher resolution compared to the other two; but its samples must be close to the X-ray source, so microCT analysis is limited to post-mortem or resected lung tissue.

Worldwide, a vast number of formalin-fixed, paraffin-embedded tuberculosis lung specimens from decades of research are available. The Steyn research team showed that microCT is able to directly characterize calcium deposits, as well as necrotic and partially calcified necrotic granulomas in those specimens. Further, they found that removing the paraffin allowed visualization of more detailed microanatomical features.

“We anticipate that microCT could be used to establish a three-dimensional reference atlas of the human tuberculous lung derived from digitized 3D image libraries of tissue, organs from new patients and existing fixed-tissue libraries,” Steyn said. “This atlas could be used to identify novel imaging biomarkers. Also, we expect an atlas of tuberculosis and COVID-19 lesion types will inform our understanding of the failure of localized immunity and be an important resource for therapeutic and diagnostic development.”

Journal reference:

Wells, G., et al. (2022) A high-resolution 3D atlas of the spectrum of tuberculous and COVID-19 lung lesions. EMBO Molecular Medicine. doi.org/10.15252/emmm.202216283.

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a …

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a link between a disorder and the community of gut microbes, and has begun to identify specific organisms that are responsible for certain conditions. Scientists have now shown that a strain of bacteria in the Subdoligranulum genus can lead to the production of autoantibodies, which appears to cause the development of rheumatoid arthritis. The findings have been reported in Science Translational Medicine.

Image cresit: Pixabay

Rheumatoid arthritis is an autoimmune disease in which the joints are erroneously attacked by the immune system, and the inflammation and damage that occurs in affected joints causes pain, the loss of mobility, and other serious problems. Disruption of mucosal immunity, in the gut, has been proposed to be one cause of rheumatoid arthritis.

In this work, the researchers obtained blood samples from people who are at risk of developing RA, and the autoantibodies were isolated from those samples.

The scientists found that the autoantibodies were causing a response in certain bacteria in the Lachnospiraceae/Ruminococcaceae families. Further work revealed that bacteria of the genus Subdoligranulum, a member of those families that was isolated from the feces of people ate risk for RA, could bind to the autoantibodies and cause the activation of CD4+ T cells. This was occurring in individuals with RA, but not in healthy people.

The Subdoligranulum bacteria was put in an animal model, and the animals began to develop the same RA risk markers found in the blood of people who are at risk for RA. Some of the animals also developed RA.

“Through studies in humans and animal models, we were able to identify these bacteria as being associated with the risk for developing RA. They trigger an RA-like disease in the animal models, and in humans, we can show that this bacterium seems to be triggering immune responses specific to RA,” said study leader Kristine Kuhn, MD, Ph.D., an associate professor at CU School of Medicine.

This microbe could be a good therapeutic target for RA treatment, noted Kuhn. Now, the scientists want to assess large populations of people who are at risk for RA to see if the Subdoligranulum microbes are also linked to other factors like genetics, mucosal immunity, and environmental conditions that can lead to RA. It may help scientists find prevention strategies or other ways to stop the microbes from causing disease, added Kuhn.

Sources: CU Anschutz Medical Campus, Science Translational Medicine

Carmen Leitch

Mycobacterium avium complex (MAC) bacteria can be found everywhere, so almost everyone breathes some of it in occasionally. …

Mycobacterium avium complex (MAC) bacteria can be found everywhere, so almost everyone breathes some of it in occasionally. While these microbes are related to deadly Mycobacterium tuberculosis, MAC tends to be harmless, existing in soil, water, dust, or even food without causing problems for most people. But sometimes, the opportunistic MAC makes someone very ill. MAC can take advantage when a person has risk factors like a structural lung disease or cystic fibrosis that make illness from MAC infections more likely, noted Cecilia Lindestam Arlehamn, Ph.D., Research Assistant Professor at La Jolla Institute for Immunology (LJI).

Mycobacterium avium, commonly found in water and soil, growing in a Petri dish. / Credit: CDC/ Dr. George Kubica

For the first time, researchers in the Lindestam Arlehamn laboratory have now revealed one reason why some people get so sick from MAC. They identified a defect in immune cells, which causes a reduction in the levels of specialized Th1* (Th1 star) cells. People who do not produce enough Th1* cells cannot effectively attack MAC bacteria, and they develop an illness. The findings have been reported in Frontiers in Immunology, and they could help create biomarkers that identify those at risk, or ways to treat the infection.

“We think these people have this cellular defect going into MAC exposure,” explained Lindestam Arlehamn.

While T cells are normally the ones that respond to an infection, work by Lindestam Arlehamn and colleagues showed that T cells have only a limited response to a MAC infection, which is very unusual.

But this research did highlight a problem that might be to blame for MAC infection illness in some people. There were significant differences in gene expression in people who had previously had an active, symptomatic MAC infection compared to healthy individuals. People who had experienced MAC illness also carried an immunological defect leading to low Th1* cell levels. Normally, Th1* cells can alert the body to danger posed by a pathogen.

The Th1* defect seems to leave carriers vulnerable to disease. The researchers suggested that when there are not enough Th1* cells, some other crucial immune cells are never alerted about the MAC invasion, and an immune response is not activated. So people susceptible to MAC infection may have innate immunity that is overly responsive, while the adaptive response is not adequate, suggested the researchers.

In individuals with other conditions, such as cystic fibrosis, the burden is too high to overcome. Thick mucus in the lungs could impede T cells’ ability to detect and attack MAC, while the lack of Th1* cells causes additional weakening of the immune response.

Now, the researchers want to confirm that people with fewer Th1* cells had the cellular defect before their MAC infection happened, as well as comparing people in a shared environment who were exposed to the same MAC, to look for differences in how T cells respond. Scientists want to solve the mystery of how MAC goes from harmless to harmful.

Sources: La Jolla Institute of Immunology, Frontiers in Immunology

Carmen Leitch