• Battling Bartonellosis

Bartonella and Connective Tissue Disorders

Disseminated, chronic forms of bartonella can cause a myriad of sequela (complications and syndromes). Bartonella is an intracellular pathogen with many adaptations and pathogenic strategies. One of those strategies involves using our host cytokine pathways for it’s own benefit. Cytokines are responsible for signaling inflammation. When Bartonella gains access to the human circulatory system, it can colonize secondary infections in locations distant and remote from the primary site of exposure (ie- away from the location of the initial cat bite, cat scratch, flea bite, etc). It targets and infects a multitude of cells in the body (including CD34+, fibroblasts, monocytes, macrophages, red blood cells, microglial cells, dendritic cells and endothelial cells). These characteristics allow this bacteria to manipulate our cellular function, but also subvert our immune system; This leads to unrivaled systemic involvement affecting multiple organ systems.


Connective tissue is a prime example. It is one of the most vast networks of tissue supporting our body and an environment that Bartonella thrives in. Bartonella targets collagen, connective tissue’s ground substance (the extracellular matrix) and certain cells that live there. Because of this, many patients suffering from bartonellosis have profound rheumatic (joint and muscle) symptoms, neurologic abnormalities, and immune dysfunction.

This often mimics auto-immune diseases like Lupus, Rheumatoid Arthritis, Scleroderma and Multiple Sclerosis. The impact is chronic inflammation. The collateral of chronic inflammation is tissue injury. This contributes to the development of bursitis, tendinosis, meniscal instability, joint pain, migraines, bone pain and neuropathy in bartonella positive patients.


The primary interest of this piece is the connection between Bartonella and Undifferentiated Connective Tissue Disorders (UCTD). Before we dive into that, the best place to start is explaining what connective tissue is and why it is important.


What is Connective Tissue?

Connective tissue is present throughout our entire body; It is exactly like it sounds…tissue involved in connection. Specifically the connection between our vascular system, muscles, joints, and nervous system. It is what gives our body function and structural reinforcement. This tissue is responsible for holding our organs in place. It is our ligaments, tendons, fatty tissue, bone, skin, lymphatic system and vascular system. It surrounds our nerves in a protective sheath. In addition to structural support, connective tissue also plays an important role in metabolic function. Scattered throughout this tissue are multiple regenerative and immune cells (macrophages, mast cells, eosinophils, and plasma cells). They are responsible for mounting an inflammatory immune response to any perceived threat or antigen. It assists in clearing cellular waste products while providing a means for essential nutrient and oxygen delivery. These connective structures are vital to our survival and existence.


What makes up connective tissue?

The 3 major components of connective tissue are fibers (like collagen and elastin), a ground substance or scaffold (the extracellular matrix or ECM) and a multitude of cells. Collagen and elastin concentrations play a key role in regulating cellular function.


Collagen is the most abundant protein in the body. It is found in our skin, muscles, tendons/ligaments, bones and blood vessels. It provides rigidity, the “glue” if you will. Collagen is connected to the extracellular matrix through cell adhesion proteins like fibronectin and glycoproteins. Elastin can be thought of as flexible “elastic fibers’ and is about 1000 times more flexible than collagen. That flexibility gives tissue resiliency, pliability, and recoil. The most obvious example is your skin.


The ECM is a complex, multidimensional network that serves as a “home” for our cells to grow, thrive and migrate. This is imperative for cell survival, nutrient exchange, regeneration, and healing. Wherever there is connective tissue, there is an ECM. Many other proteins, growth factors, biochemicals and macromolecules exist within this matrix and it can vary from system to system. For example, the primary ECM component in the brain is hyaluronic acid.


The ECM is dynamic and undergoing construction, either building up the scaffolding (by using growth factors like VEGF, epidermal growth factors, fibroblasts) or breaking it down (by using Matrix Metalloproteinases or MMPs, or other various proteases). It all depends on the physiologic conditions of the body, conditions bartonella can manipulate. Any resultant alterations in the ECM will influence function of organs and tissues.


While this is an oversimplified explanation it gives you a good base to better understand the significance of connective tissue disorders.


What is an Undifferentiated Connective Tissue Disorder (UCTD)?

Disorders of connective tissue can be broken down into differentiated, mixed or undifferentiated. Most patients with bartonellosis will fall into the category of ‘mixed’ or ‘undifferentiated’. In general, the term UCTD describes the situation where patients have evident symptoms of connective tissue disease but do not meet criteria to diagnose any of the known connective tissue disorders. The symptoms, features and lab results will be supportive of auto-immune dysfunction (ie-likened to Systemic Lupus, Scleroderma, RA), but not enough to differentiate or define it further, hence the term “Undifferentiated”.


Given our vast network of connective tissue, patients can develop a multitude of secondary injuries. This can include injury to the lungs, heart, kidneys, intestinal tract, musculoskeletal system, reproductive tract, thyroid, auditory and sensory system, central and peripheral nervous system and result in hematologic abnormalities like anemia (low red blood cell count), thrombocytopenia (low platelets) and leukopenia (low white blood cell count). It can lead to a plethora of symptoms, severely affecting quality of life, and limiting function.


Treatment focuses on decreasing the symptoms but sadly, does not focus on treating the process causing the symptoms since one could not be found.


What are the possible symptoms?

Are you seeing the theme here?? Many of these symptoms overlap with Mast Cell Activation Syndrome, Small Vessel Inflammatory Disease (vasculitis) and Vector-Borne Disease (coined ‘stealth pathogens’)


Possible Causes:

The classification depends on the findings of your work-up with a doctor. There are more than 200 different types of connective tissue disease. Most of the time, the cause is not well known even though the disease they cause is. Possible causes include:

  1. Hereditary (caused by family genetics)

  2. Caused by interactions within an environment (environmental factors)

  3. Both (a genetic predisposition exists which is later triggered by an environmental factor).

Within all are basic themes of chronic inflammation, vasculitis and auto-immune disease. Types of Ehlers-Danlos Syndrome and Marfan Syndrome are good examples of hereditary acquisition. Environmental factors are broad, but can include one or more of the following:

  1. Nutrient deficiencies (vitamin, mineral)

  2. Exposure to toxic chemicals

  3. Exposure to UV light

  4. Infection (like bartonella, mycoplasma, Lyme disease, viruses, parasitic and fungal)

How does Bartonella Assist in Development of Connective Tissue Disease?

Many patients with Bartonellosis experience a variety of connective tissue derangements. The reason for this is Bartonella’s ability to manipulate host inflammation which targets our connective tissue’s extracellular matrix and collagen. Remember the theme here is inflammation. The downside to chronic inflammation is collateral damage to tissue --> bartonella uses, creates, manipulates, and exacerbates inflammation = disruption of our balance between good and bad inflammation = a pro-inflammatory state = tissue damage, in this case specifically connective tissue.


There are multiple pathogenic strategies:

The use of our extracellular matrix and connective tissue proteins:

  • Bartonella is highly abundant in connective tissue and creates adhesions in the extracellular matrix via host proteins with collagen, laminin, fibronectin, integrins (all found in the ECM)

  • Bartonella has specific surface proteins known as adhesins. Examples include Pap31, BadA (Bartonella Adhesin A), TAAs (Trimeric Autotransporter Adhesins) which allow bartonella to bind to the collagen, fibronectin (a glycoprotein) and heparin (a glycosaminoglycan); all are found in our ECM.

  • Research has shown it has an affinity to bind to Collagen (specifically type 9 and 10, possibly Collagen type 4)

  • Bartonella is also thought to bind to vitronectin (a glycoprotein needed for tissue remodeling) and hyaluronic acid (which keeps are tissues well lubricated and moist). In the brain hyaluronic acid is the main component of the ECM. When Hyaluronic acid is degraded it causes pro-inflammatory response by using microglial cells (another cell bartonella is known to invade)

  • Bartonella stimulated cytokines control aspects of our innate immune response. Through a series of interactions, bartonella intentionally induces an inflammatory response releasing substances like Interleukin-8 (IL-8) into the ECM. This cytokine is one of the major substances necessary for mounting an inflammatory response, which bartonella thrives in. This can lead to endothelial proliferation (reproduction of cells that line the inside of blood vessels and lymphatic vessels), inhibition of our host cells to undergo apoptosis (decreases a cell's ability to undergo programmed and controlled cell death), stimulation of endothelial migration (increases new capillary or blood source formation) and increased epidermal growth factor (stimulates the growth of different cell types like fibroblasts and epithelial cells).

  • Bartonella’s use of IL-8 upregulates MMP-2 and MMP-9 which breakdown parts of our ECM and collagen. Damaged collagen tissue then recruits CD34+ (Hematopoietic Progenitor Cells) to the site of damage. Remember that CD34+ cells are another cell that Bartonella infects…this allows them to take advantage of local inflammation

  • Not only does it exploit our natural host interactions to cause inflammation and cellular recruitment, but it also uses existing inflammation in our body to seed new infections.

  • Existing inflammation facilitates bartonella growth --> Bartonella begins to produce their own cytokine cascade which means more collagen breakdown and the cycle continues

  • Once these infections are established within our ECM, the colonies of bartonella are protected, further subverting our immune detection. This is one of the proposed niches for infection.

Mast Cell Activation:

  • Another proposed mechanism of connective tissue disease is mast cell dysfunction (seen with Mast Cell Activation Syndrome or MCAS). Many patients with Bartonellosis also exhibit symptoms of MCAS. Research proposed that mast cell activation and dysregulation plays an role in a subset of “nongenetically mediated Ehlers-Danlos Syndromes (EDS) with joint hypermobility”. Meaning it affects the connective tissue and appears similar to EDS, but is not genetic. This proposed mechanism implies that MCAS cause alterations in collagen formation.

  • Mast cells are primarily found in connective tissue and are in charge of releasing inflammatory mediators in response to a perceived threat. Many of these mediators are fibrogenic which can lead to tissue scarring and fibrosis.

  • Mast cells communicate intimately with the central and peripheral nervous system through our connective tissues.

  • Each nerve is surrounded by multiple layers of connective tissue. The outer most layer is called an epineurium and each axon (or dendrite) is surrounded by another type of connective tissue called an endoneurium (which protects our peripheral nerves) and myelin sheath. Axons or dendrites allow our nerve cell or neurons to communicate with other cells. In these regions there are also circulating mast cells, mast cells that may be dysfunctional (as seen with MCAS). Bartonella also invades and infects cells of our nervous system, specifically Microglial Cells. These cells help mediate the CNS immune response by clearing cellular debris and injured/dead neurons. Add this to bartonella’s use of MMP’s which assist in the breakdown of collagen = The result of these factors is damage to our nerve sheaths which can mimic diseases like Multiple Sclerosis and lead to a number of neurologic symptoms. This is something the National Multiple Sclerosis Society recognizes with Lyme Disease.

What does the general work-up consist of?

Generally, a rheumatologist is recommended. It is important to pursue a full work-up to rule out possible causes and to help determine disease you may be suffering from. It is also important for patients with connective tissue disease to have routine evaluations monitoring for progression. A comprehensive medical and family history are needed. Discussion of symptomatology is key then your doctor will perform a physical exam.


Once suspicion is established, there are many supportive tests that can be ordered to classify (differentiate) what time of connective tissue you may have.


This can include:

  • Basic bloodwork (Complete blood count, Urinalysis, Chemistry profile)

  • Testing inflammatory markers: ANA, CRP, ESR, VEGF, TGF-B1, anti-SM antibodies, anti-DNA antibodies and all tests specific to each possible auto-immune condition.

  • Thyroid panel evaluating for Hashimoto’s Hypothyroiditis

  • Baseline EKG and Heart Scan (Echocardiogram) will assess cardiopulmonary function

  • Pulmonary Function tests to evaluate connective tissue in the lungs

  • Imaging of areas of concern via x-rays, abdominal ultrasound or MRI

  • Genetic Testing

  • Evaluating tissue biopsies, blood and urine

  • Evaluating for infection like Vector-borne illness (Lyme, Bartonella, etc) via traditional IFA and advanced microbial testing available at Galaxy Diagnostics.

What is the treatment?

The goal of treatment is to control symptoms, reduce the risk progressing complication from said disorder and to assist in maintaining function and quality of life. If a root cause is identified, like an infection, deficiencies, etc then appropriate treatment for that is required. Treatment is otherwise aimed at controlling the various targets of disease specific to each organ involved. Actively monitoring for progression is imperative.


General options for UCTD

  • Prescription Pain medications

  • Topical Steroids and Pain Creams

  • Antimalarial pills such as hydroxychloroquine

  • Immunosuppressive Drugs:

  • DMARDS (Disease-Modifying Antirheumatic Drugs): methotrexate, azathioprine

  • High Dose Oral Steroids (prednisone)

  • Both are contraindicated with infection

  • NSAIDS (prescription or over-the-counter)

  • Natural anti-inflammatories like Curcumin and Quercetin

  • Correcting any nutrient deficiencies that may be present

  • Treatment of any underlying infections

  • Proton Pump Inhibitors for gastric reflux

Wondering how this might look in a patient??

Check out how it relates to my clinical picture:

Joint and Muscle Progression (2017-current)

Neurologic Progression (2019-current)


Support Groups:

  1. The Ehlers-Danlos Society: Connect with others

  2. The Mixed Connective Tissue Disease Foundation

Additional patient resources:

  1. Understanding Bartonellosis

  2. Rheumatology Advisors: Undifferentiated Connective Tissue disease

  3. Mixed Connective Tissue Disease, Merck Manual Professional Version

  4. Lyme Disease, Co-Infections & The Assault on your Connective Tissue

  5. The Extracellular Matrix: Key to unraveling Chronic Disease?

  6. Healing Lyme Disease Coinfections: Complementary and Holistic Treatments for Bartonella and Mycoplasma by Stephen Harrod Buhner (Highly recommend this book)

Research:

  1. Binding of Bartonella henselae to extracellular molecules: identification of potential adhesins. Journal of Microbial Pathogenesis, July 2006

  2. Interaction with the host: the role of fibronectin and extracellular matrix proteins in the adhesion of Gram-negative bacteria. Journal of Medical Microbiology and Immunology, June 2020

  3. High prevalence of gluten sensitivity in a cohort of patients with undifferentiated connective tissue disease. European Annals of Allery and Clinical Immunology, March 2015

  4. Bartonella henselae Pap31, an Extracellular Matrix Adhesin, Binds the Fibronectin Repeat III13 Module. Journal of Infectious Immunology, May 2006

  5. An Immunocompromised Murine Model of Chronic Bartonella Infection. The American Journal of Pathology: Cellular and Molecular Biology of Disease, June 2010

  6. Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias. A case report, April 2018

  7. The head of Bartonella adhesin A is crucial for host cell interaction of Bartonella henselae. The Journal of Cellular Microbiology. November 2008

  8. Adhesins of Bartonella spp. Journal of Advances in experimental medicine and biology. 2011

  9. Adhesion and host cell modulation: critical pathogenicity determinants of Bartonella henselae. Journal of Parasites and Vectors. April 2011

  10. Bartonella entry mechanisms into mammalian host cells. Journal of Cellular Microbiology, Aug 2012


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